N-(amino-heteroaryl)-1H-pyrrolopyridine-2-carboxamides derivatives preparation thereof and their use in therapy

ABSTRACT

The invention relates to compounds of the general formula (I): 
     
       
         
         
             
             
         
       
     
     Wherein X, Y, Z, Z 1 , Z 2 , Z 3 , Z 4  and n are as defined herein. The invention also relates to a method for making the same and to the use thereof in therapy.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No.12/489,672, filed Jun. 23, 2009, now allowed, which is a continuation ofInternational application No. PCT/FR2007/002122, filed Dec. 20, 2007,which is incorporated herein by reference in its entirety; which claimsthe benefit of priority of French Patent Application No. 06/11353, filedDec. 26, 2006.

BACKGROUND OF THE INVENTION Field of the Invention

The invention relates to compounds derived fromN-(amino-heteroaryl)-1H-pyrrolopyridine-2-carboxamides, which displayantagonist activity in vitro and in vivo for type TRPV1 (or VR1)receptors.

A first object of the invention relates to compounds corresponding togeneral formula (I) given below.

Another object of the invention relates to methods of preparation of thecompounds of general formula (I).

Another object of the invention relates to the use of the compounds ofgeneral formula (I) notably in medicinal products or in pharmaceuticalcompositions.

SUMMARY OF THE INVENTION

The compounds of the invention correspond to general formula (I):

in which

the pyrrolopyridine nucleus is a pyrrolo[3,2-b]pyridine group, apyrrolo[3,2-c]pyridine group, a pyrrolo[2,3-c]pyridine group or apyrrolo[2,3-b]pyridine group;

-   -   the pyrrolopyridine nucleus being optionally substituted in        carbon position 4, 5, 6 and/or 7 with one or more substituents        X, which may be identical to or different from one another,        selected from a hydrogen or halogen atom or a C₁-C₆-alkyl,        C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkylene,        C₁-C₆-fluoroalkyl, C₁-C₆-alkoxyl, C₃-C₇-cycloalkoxyl,        C₃-C₇-cycloalkyl-C₁-C₆-alkylene-O—, C₁-C₆-fluoroalkoxyl, cyano,        C₁-C₆-thioalkyl, —S(O)—C₁-C₆-alkyl, —S(O)₂—C₁-C₆-alkyl, SF₅,        C(O)NR₁R₂, SO₂NR₁R₂, nitro, NR₁R₂, OCONR₁R₂, NR₃COR₄,        NR₃CONR₁R₂, NR₃SO₂R₅, NR₃SO₂NR₁R₂, aryl-C₁-C₆-alkylene,        heteroaryl-C₁-C₆-alkylene, aryl or heteroaryl group, the aryl        and the heteroaryl being optionally substituted with one or more        substituents selected from a halogen, a C₁-C₆-alkyl,        C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkylene,        C₁-C₆-fluoroalkyl, C₁-C₆-alkoxyl, C₁-C₆-fluoroalkoxyl, nitro or        cyano group;

n is equal to 0, 1, 2 or 3;

Y represents an aryl or a heteroaryl,

-   -   the aryl or the heteroaryl being optionally substituted with one        or more groups selected from a halogen atom or a C₁-C₆-alkyl,        C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkylene,        C₁-C₆-fluoroalkyl, hydroxyl, C₁-C₆-alkoxyl, C₃-C₇-cycloalkoxyl,        C₃-C₇-cycloalkyl-C₁-C₆-alkylene-O—, C₁-C₆-fluoroalkoxyl, cyano,        C₁-C₆-thioalkyl, thiol, —S(O)—C₁-C₆-alkyl, —S(O)₂—C₁-C₆-alkyl,        C(O)NR₁R₂, SO₂NR₁R₂, SF₅, nitro, OCONR₁R₂, NR₃COR₄, NR₃CONR₁R₂,        NR₁R₂, NR₃SO₂NR₁R₂, NR₃COR₄, NR₃SO₂R₅, aryl-C₁-C₆-alkylene or        aryl group, the aryl and the aryl-C₁-C₆-alkylene being        optionally substituted with one or more substituents selected        from a halogen, a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,        C₃-C₇-cycloalkyl-C₁-C₆-alkylene, C₁-C₆-fluoroalkyl,        C₁-C₆-alkoxyl, C₁-C₆-fluoroalkoxyl, nitro or cyano group;

Z₁, Z₂, Z₃, Z₄ represent, independently of one another, a nitrogen atomor a group C(R₆), at least one corresponding to a nitrogen atom and atleast one corresponding to a group C(R₆); the nitrogen atom or one ofthe nitrogen atoms present in the ring, defined as position-1 nitrogen,being optionally substituted with R₇ when the carbon atom in position 2or 4 relative to this reference nitrogen is substituted with an oxo orthio group;

Z represents

either a cyclic amine attached by the nitrogen atom, of formula:

in which

-   -   A represents a C₁-C₇-alkylene group optionally substituted with        one or two groups R₈    -   B represents a C₁-C₇-alkylene group optionally substituted with        one or two groups R₉;    -   L represents a linkage, a sulfur, oxygen or nitrogen atom; the        nitrogen atom being optionally substituted with a group R₁₀ or        R₁₁;

the carbon atoms of the cyclic amine Z being optionally substituted withone or more groups R₁₂ which may be identical to or different from oneanother;

or an acyl amine, attached by the nitrogen atom, of formula NRaRb inwhich Ra and Rb represent, independently of one another, a hydrogen atomor a C₁-C₆-alkyl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkylene,C₁-C₆-fluoroalkyl, hydroxyl, C₁-C₆-alkoxyl,C₃-C₇-cycloalkyl-C₁-C₆-alkylene-O—, C₁-C₆-fluoroalkoxyl,C₁-C₆-alkyl-C(O)—, HO—C(O)—C₁-C₆-alkylene,C₁-C₆-alkyl-O—C(O)—C₁-C₆-alkylene, aryl or heteroaryl group, and Ra andRb can optionally be substituted with one or more groups Rc which may beidentical to or different from one another;

Rc represents a halogen atom, a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₆-alkylene, C₁-C₆-fluoroalkyl, C₁-C₆-alkoxyl,C₃-C₇-cycloalkyl-C₁-C₆-alkylene-O—, C₁-C₆-fluoroalkoxyl,C₁-C₆-thioalkyl, —S(O)—C₁-C₆-alkyl, —S(O)₂—C₁-C₆-alkyl, cyano,C(O)NR₁R₂, NR₁R₂, SO₂NR₁, R₂, NR₃COR₄, NR₃SO₂R₅, OC(O)NR₁R₂, NR₃COOR₅,NR₃CONR₁R₂, NR₃SO₂NR₁R₂, hydroxyl, thiol, oxo, thio,aryl-C₁-C₆-alkylene, aryl or heteroaryl group, the aryl and theheteroaryl being optionally substituted with one or more substituentsselected from a halogen, a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₆-alkylene, C₁-C₆-fluoroalkyl, C₁-C₆-alkoxyl,C₁-C₆-fluoroalkoxyl, nitro or cyano group;

R₁ and R₂ represent, independently of one another, a hydrogen atom or aC₁-C₆-alkyl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkylene,aryl-C₁-C₆-alkylene, aryl or heteroaryl group, the aryl and theheteroaryl being optionally substituted with one or more substituentsselected from a halogen, a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₆-alkylene, C₁-C₆-fluoroalkyl, C₁-C₆-alkoxyl,C₁-C₆-fluoroalkoxyl, nitro or cyano group; or

R₁ and R₂ together form, with the nitrogen atom by which they arecarried, an azetidinyl, pyrrolidinyl, piperidinyl, azepinyl,morpholinyl, thiomorpholinyl, piperazinyl, homopiperazinyl group, saidgroup being optionally substituted with a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₆-alkylene, aryl-C₁-C₆-alkylene, aryl or heteroarylgroup, the aryl and the heteroaryl being optionally substituted with oneor more substituents selected from a halogen, a C₁-C₆-alkyl,C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkylene, C₁-C₆-fluoroalkyl,C₁-C₆-alkoxyl, C₁-C₆-fluoroalkoxyl, nitro or cyano group;

R₃ and R₄ represent, independently of one another, a hydrogen atom or aC₁-C₆-alkyl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkylene,aryl-C₁-C₆-alkylene, aryl or heteroaryl group, the aryl and theheteroaryl being optionally substituted with one or more substituentsselected from a halogen, a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₆-alkylene, C₁-C₆-fluoroalkyl, C₁-C₆-alkoxyl,C₁-C₆-fluoroalkoxyl, nitro or cyano group;

or R₃ and R₄ together form a (C₂-C₅)alkylene group;

or R₁ and R₃ together form a (C₂-C₅)alkylene group;

R₅ represents a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₆-alkylene, aryl-C₁-C₆-alkylene, aryl or heteroarylgroup, the aryl and the heteroaryl being optionally substituted with oneor more substituents selected from a halogen, a C₁-C₆-alkyl,C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkylene, C₁-C₆-fluoroalkyl,C₁-C₆-alkoxyl, C₁-C₆-fluoroalkoxyl, nitro or cyano group;

or R₃ and R₅ together form a (C₂-C₅)alkylene group;

R₆ represents a hydrogen or halogen atom or a C₁-C₆-alkyl,C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkylene, C₁-C₆-fluoroalkyl,C₁-C₆-alkoxyl, C₃-C₇-cycloalkoxyl, C₃-C₇-cycloalkyl-C₁-C₆-alkylene-O—,C₁-C₆-fluoroalkoxyl, C₁-C₆-thioalkyl, —S(O)—C₁-C₆-alkyl,—S(O)₂—C₁-C₆-alkyl, hydroxyl, thiol, oxo, thio, aryl,aryl-C₁-C₆-alkylene, heteroaryl group, the aryl and the heteroaryl beingoptionally substituted with one or more substituents selected from ahalogen, a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₆-alkylene, C₁-C₆-fluoroalkyl, C₁-C₆-alkoxyl,C₁-C₆-fluoroalkoxyl, nitro or cyano group;

R₇ represents a hydrogen atom, a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₆-alkylene, C₁-C₆-fluoroalkyl, C₁-C₆-alkoxyl,C₃-C₇-cycloalkoxyl, C₃-C₇-cycloalkyl-C₁-C₆-alkylene-O—,C₁-C₆-fluoroalkoxyl, aryl, aryl-C₁-C₆-alkylene or heteroaryl group, thearyl and the heteroaryl being optionally substituted with one or moresubstituents selected from a halogen, a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₆-alkylene, C₁-C₆-fluoroalkyl, C₁-C₆-alkoxyl,C₁-C₆-fluoroalkoxyl, nitro or cyano group;

R₈, R₉ and R₁₀ are defined such that:

two groups R₈ can together form a linkage or a C₁-C₆-alkylene group;

two groups R₉ can together form a linkage or a C₁-C₆-alkylene group;

R₈ and R₉ can together form a linkage or a C₁-C₆-alkylene group;

R₈ and R₁₀ can together form a linkage or a C₁-C₆-alkylene group;

R₉ and R₁₀ can together form a linkage or a C₁-C₆-alkylene group;

R₁₁ represents a hydrogen atom, a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₆-alkylene, C₁-C₆-fluoroalkyl, C₁-C₆-alkoxyl,C₃-C₇-cycloalkoxyl, C₃-C₇-cycloalkyl-C₁-C₆-alkylene-O—,C₁-C₆-fluoroalkoxyl, hydroxyl, C₁-C₆-alkyl-CO—, COOR₅, C(O)NR₁R₂,aryl-C₁-C₆-alkylene, aryl or heteroaryl group, the aryl and theheteroaryl being optionally substituted with one or more substituentsselected from a halogen, a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₆-alkylene, C₁-C₆-fluoroalkyl, C₁-C₆-alkoxyl,C₃-C₇-cycloalkoxyl, C₁-C₆-fluoroalkoxyl, nitro or cyano group;

R₁₂ represents a fluorine atom, a C₁-C₆-alkyl group optionallysubstituted with an R₁₃, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₆-alkylene, C₁-C₆-fluoroalkyl,C₁-C₆-cycloalk-1,1-diyl, C₃-C₇-heterocycloalk-1,1-diyl group optionallysubstituted on a nitrogen atom with an R₁₁, C₁-C₆-alkoxyl,C₃-C₇-cycloalkoxyl, C₃-C₇-cycloalkyl-C₁-C₆-alkylene-O—,C₁-C₆-fluoroalkoxyl, CO₂H, C(O)O—C₁-C₆-alkyl, C(O)NR₁R₂, NR₁R₂, NR₃COR₄,OC(O)NR₁R₂, NR₃COOR₅, NR₃CONR₁R₂ hydroxyl, thiol, oxo, thio,aryl-C₁-C₆-alkylene, aryl group, the aryl being optionally substitutedwith one or more substituents selected from a halogen, a C₁-C₆-alkyl,C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkylene, C₁-C₆-fluoroalkyl,C₁-C₆-alkoxyl, C₃-C₇-cycloalkoxyl, C₁-C₆-fluoroalkoxyl, nitro or cyanogroup;

R₁₃ represents a C₁-C₆-alkoxyl, C₃-C₇-cycloalkoxyl,C₃-C₇-cycloalkyl-C₁-C₆-alkylene-O—, C(O)NR₁R₂, NR₁R₂, NR₃COR₄,OC(O)NR₁R₂, NR₃COOR₅, hydroxyl group.

In the compounds of general formula (I), the nitrogen atom or atoms canbe in oxidized form (N-oxide).

DETAILED DESCRIPTION OF THE INVENTION

Among the compounds of general formula (I) according to the invention, afirst subgroup of compounds comprises compounds for which thepyrrolopyridine nucleus is a pyrrolo[3,2-b]pyridine group, apyrrolo[2,3-c]pyridine group or a pyrrolo[2,3-b]pyridine group.

Among the compounds of general formula (I) according to the invention, asecond subgroup of compounds comprises compounds for which, if n isequal to 0, then the substituent or substituents X, which may beidentical to or different from one another, are selected from a hydrogenor halogen atom or a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₆-alkylene, C₁-C₆-fluoroalkyl, C₁-C₆-alkoxyl,C₃-C₇-cycloalkoxyl, C₃-C₇-cycloalkyl-C₁-C₆-alkylene-O—,C₁-C₆-fluoroalkoxyl, cyano, C₁-C₆-thioalkyl, —S(O)—C₁-C₆-alkyl,—S(O)₂—C₁-C₆-alkyl, SF_(S), C(O)NR₁R₂, SO₂NR₁R₂, nitro, NR₁R₂, OCONR₁R₂,NR₃COR₄, NR₃CONR₁R₂, NR₃SO₂R₅, NR₃SO₂NR₁R₂ group.

Among the compounds of general formula (I) according to the invention, athird subgroup of compounds comprises compounds for which, when n=0 or1, Y is different from a bare phenyl.

Among the compounds of general formula (I) according to the invention, afourth subgroup of compounds comprises compounds for which thesubstituent or substituents X, which may be identical to or differentfrom one another, are selected from a hydrogen or halogen atom, moreparticularly a fluorine atom, or a C₁-C₆-fluoroalkyl group, moreparticularly trifluoromethyl.

Among the compounds of general formula (I) according to the invention, afifth subgroup of compounds comprises compounds for which n is equal to1.

Among the compounds of general formula (I) according to the invention, asixth subgroup of compounds comprises compounds for which Y representsan aryl, more particularly a phenyl, or a heteroaryl, more particularlya pyridinyl, the aryl or the heteroaryl being optionally substitutedwith one or more, more particularly with one or two, groups selectedfrom a halogen atom, more particularly a fluorine or chlorine atom, or aC₁-C₆-alkyl group, more particularly methyl, C₁-C₆-fluoroalkyl group,more particularly trifluoromethyl, C₁-C₆-alkoxyl group, moreparticularly methoxy, C₁-C₆-fluoroalkoxyl group, more particularlytrifluoromethoxy.

Among the compounds of general formula (I) according to the invention, aseventh subgroup of compounds comprises compounds for which Z₁, Z₂, Z₃,Z₄ represent, independently of one another, a nitrogen atom or a groupC(R₆), at least one corresponding to a nitrogen atom and at least onecorresponding to a group C(R₆);

R₆ represents a hydrogen or halogen atom, more particularly a fluorineatom, or a C₁-C₆-alkyl group, more particularly a methyl,C₁-C₆-fluoroalkyl group, more particularly a trifluoromethyl orC₁-C₆-alkoxyl group, more particularly methoxy.

Among the compounds of general formula (I) according to the invention,an eighth subgroup of compounds comprises compounds for which Zrepresents either a cyclic amine attached by the nitrogen atom, offormula:

in which

-   -   A represents a C₁-C₇-alkylene group optionally substituted with        one or two groups R₈;    -   B represents a C₁-C₇-alkylene group optionally substituted with        one or two groups R₉;    -   L represents a linkage;

the carbon atoms of the cyclic amine Z being optionally substituted withone or more groups R₁₂ which may be identical to or different from oneanother; R₁₂ represents a fluorine atom, a C₁-C₆-alkyl, C₁-C₆-alkoxyl,C₃-C₇-cycloalkyl-C₁-C₆-alkylene-O—, CO₂H, C(O)O—C₁-C₆-alkyl or hydroxylgroup;

R₈ and R₉ are defined such that:

two groups R₈ can together form a linkage or a C₁-C₆-alkylene group;

two groups R₉ can together form a linkage or a C₁-C₆-alkylene group;

R₈ and R₉ can together form a linkage or a C₁-C₆-alkylene group;

or an acyl amine, attached by the nitrogen atom, of formula NRaRb inwhich Ra and Rb represent, independently of one another, a hydrogen atomor a C₁-C₆-alkyl, C₁-C₆-alkyl-C(O)—, HO—C(O)—C₁-C₆-alkylene orC₁-C₆-alkyl-O—C(O)—C₁-C₆-alkylene group, and Ra and Rb can optionally besubstituted with a group Rc where Rc represents a hydroxyl.

Among the compounds of general formula (I) according to the invention, aninth subgroup of compounds comprises compounds for which Z representseither a cyclic amine attached by the nitrogen atom, of formula:

in which

-   -   A represents a C₁-C₇-alkylene group optionally substituted with        a group R₈;    -   B represents a C₁-C₇-alkylene group optionally substituted with        a group R₉,    -   L represents a linkage;

the carbon atoms of the cyclic amine Z being optionally substituted withone or more groups R₁₂ which may be identical to or different from oneanother; R₁₂ represents a fluorine atom, a C₁-C₆-alkyl, C₁-C₆-alkoxyl,C₃-C₇-cycloalkyl-C₁-C₆-alkylene-O—, CO₂H, C(O)O—C₁-C₆-alkyl or hydroxylgroup;

R₈ and R₉ are defined such that:

R₈ and R₉ can together form a linkage;

or an acyl amine, attached by the nitrogen atom, of formula NRaRb inwhich Ra and Rb represent, independently of one another, a hydrogen atomor a C₁-C₆-alkyl, C₁-C₆-alkyl-C(O)—, HO—C(O)—C₁-C₆-alkylene orC₁-C₆-alkyl-O—C(O)—C₁-C₆-alkylene group, and Ra and Rb can optionally besubstituted with a group Rc where Rc represents a hydroxyl.

Among the compounds of general formula (I) according to the invention, atenth subgroup of compounds comprises compounds for which Z represents

either a cyclic amine attached by the nitrogen atom and selected fromthe pyrrolidinyl, azetidinyl, azabicyclo[3.2.0]heptyl orazabicyclo[3.1.0]hexyl groups, the carbon atoms of the cyclic aminebeing optionally substituted with one or more groups R₁₂ which may beidentical to or different from one another; R₁₂ represents a fluorineatom, a C₁-C₆-alkyl group, more particularly methyl, C₁-C₆-alkoxylgroup, more particularly methoxy, C₃-C₇-cycloalkyl-C₁-C₆-alkylene-O—group, more particularly cyclopropyl)methyloxy, CO₂H, C(O)O—C₁-C₆-alkyl,more particularly C(O)O-ter-butyl, or hydroxyl group; or an acyl amine,attached by the nitrogen atom, of formula NRaRb in which Ra and Rbrepresent, independently of one another, a hydrogen atom or aC₁-C₆-alkyl group, more particularly methyl, propyl, isopropyl,C₁-C₆-alkyl-C(O)—, more particularly CH₃—C(O)—, HO—C(O)—C₁-C₆-alkylene,more particularly HO—C(O)—(CH₂)₂—, or C₁-C₆-alkyl-O—C(O)—C₁-C₆-alkylene,more particularly CH₃CH₂—COO—(CH₂)₂—, and Ra and Rb can optionally besubstituted with a group Rc where Rc represents a hydroxyl.

Among the compounds of the invention, an eleventh subgroup of compoundscomprises compounds of general formula (I) in which, simultaneously, thepyrrolopyridine nucleus and/or X and/or n and/or Y and/or Z₁, Z₂, Z₃, Z₄and/or Z are as defined in the above groups.

Among the compounds of general formula (I) according to the invention, atwelfth subgroup of compounds comprises compounds for which

the pyrrolopyridine nucleus is a pyrrolo[3,2-b]pyridine group, apyrrolo[2,3-c]pyridine group or a pyrrolo[2,3-b]pyridine group;

the substituent or substituents X, which may be identical to ordifferent from one another, are selected from a hydrogen or halogenatom, more particularly a fluorine atom, or a C₁-C₆-fluoroalkyl group,more particularly trifluoromethyl;

n is equal to 1;

Y represents an aryl, more particularly a phenyl, or a heteroaryl, moreparticularly a pyridinyl, the aryl or the heteroaryl being optionallysubstituted with one or more, more particularly with one or two, groupsselected from a halogen atom, more particularly a fluorine or chlorineatom, or a C₁-C₆-alkyl group, more particularly methyl,C₁-C₆-fluoroalkyl, more particularly trifluoromethyl, C₁-C₆-alkoxyl,more particularly methoxy, C₁-C₆-fluoroalkoxyl, more particularlytrifluoromethoxy;

Z₁, Z₂, Z₃, Z₄ represent, independently of one another, a nitrogen atomor a group C(R₆), at least one corresponding to a nitrogen atom and atleast one corresponding to a group C(R₆);

R₆ represents a hydrogen or halogen atom, more particularly a fluorineatom, or a C₁-C₆-alkyl group, more particularly a methyl,C₁-C₆-fluoroalkyl, more particularly a trifluoromethyl or C₁-C₆-alkoxyl,more particularly methoxy;

Z represents

either a cyclic amine attached by the nitrogen atom and selected fromthe pyrrolidinyl, azetidinyl, azabicyclo[3.2.0]heptyl orazabicyclo[3.1.0]hexyl groups, the carbon atoms of the cyclic aminebeing optionally substituted with one or more groups R₁₂ which may beidentical to or different from one another; R₁₂ represents a fluorineatom, a C₁-C₆-alkyl group, more particularly methyl, C₁-C₆-alkoxyl, moreparticularly methoxy, C₃-C₇-cycloalkyl-C₁-C₆-alkylene-O—, moreparticularly cyclopropyl)methyloxy, CO₂H, C(O)O—C₁-C₆-alkyl, moreparticularly C(O)O-ter-butyl, or hydroxyl;

or an acyl amine, attached by the nitrogen atom, of formula NRaRb inwhich Ra and Rb represent, independently of one another, a hydrogen atomor a C₁-C₆-alkyl group, more particularly methyl, propyl, isopropyl,C₁-C₆-alkyl-C(O)—, more particularly CH₃—C(O)—, HO—C(O)—C₁-C₆-alkylene,more particularly HO—C(O)—(CH₂)₂—, or C₁-C₆-alkyl-O—C(O)—C₁-C₆-alkylene,more particularly CH₃CH₂—COO—(CH₂)₂—, and Ra and Rb can optionally besubstituted with a group Rc where Rc represents a hydroxyl.

Among the compounds of general formula (I), a subfamily of compounds isrepresented by general formula (Ia):

in which

the pyrrolopyridine nucleus is a pyrrolo[3,2-b]pyridine group, apyrrolo[3,2-c]pyridine group, a pyrrolo[2,3-c]pyridine group or apyrrolo[2,3-b]pyridine group;

-   -   the pyrrolopyridine nucleus being optionally substituted in        carbon position 4, 5, 6 and/or 7 with one or more substituents        X, which may be identical to or different from one another,        selected from a hydrogen or halogen atom or a C₁-C₆-alkyl,        C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkylene,        C₁-C₆-fluoroalkyl, C₁-C₆-alkoxyl, C₃-C₇-cycloalkoxyl,        C₃-C₇-cycloalkyl-C₁-C₆-alkylene-O—, C₁-C₆-fluoroalkoxyl, cyano,        C₁-C₆-thioalkyl, —S(O)—C₁-C₆-alkyl, —S(O)₂—C₁-C₆-alkyl, SF₅,        C(O)NR₁R₂, SO₂NR₁R₂, nitro, NR₁R₂, OCONR₁R₂, NR₃COR₄,        NR₃CONR₁R₂, NR₃SO₂R₅, NR₃SO₂NR₁R₂, aryl-C₁-C₆-alkylene,        heteroaryl-C₁-C₆-alkylene, aryl or heteroaryl group, the aryl        and the heteroaryl being optionally substituted with one or more        substituents selected from a halogen, a C₁-C₆-alkyl,        C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkylene,        C₁-C₆-fluoroalkyl, C₁-C₆-alkoxyl, C₁-C₆-fluoroalkoxyl, nitro or        cyano group;

n is equal to 0, 1, 2 or 3;

Y represents an aryl or a heteroaryl,

-   -   the aryl or the heteroaryl being optionally substituted with one        or more groups selected from a halogen atom or a C₁-C₆-alkyl,        C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkylene,        C₁-C₆-fluoroalkyl, hydroxyl, C₁-C₆-alkoxyl, C₃-C₇-cycloalkoxyl,        C₃-C₇-cycloalkyl-C₁-C₆-alkylene-O—, C₁-C₆-fluoroalkoxyl, cyano,        C₁-C₆-thioalkyl, thiol, —S(O)—C₁-C₆-alkyl, —S(O)₂—C₁-C₆-alkyl,        C(O)NR₁R₂, SO₂NR₁R₂, SF₅, nitro, OCONR₁R₂, NR₃COR₄, NR₃CONR₁R₂,        NR₁R₂, NR₃SO₂NR₁R₂, NR₃COR₄, NR₃SO₂R₅, aryl-C₁-C₆-alkylene or        aryl group, the aryl and the aryl-C₁-C₆-alkylene being        optionally substituted with one or more substituents selected        from a halogen, a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,        C₃-C₇-cycloalkyl-C₁-C₆-alkylene, C₁-C₆-fluoroalkyl,        C₁-C₆-alkoxyl, C₁-C₆-fluoroalkoxyl, nitro or cyano group;

Z₁, Z₂, Z₃, Z₄ represent, independently of one another, a nitrogen atomor a group C(R₆), at least one corresponding to a nitrogen atom and atleast one corresponding to a group C(R₆); the nitrogen atom or one ofthe nitrogen atoms present in the ring, defined as position-1 nitrogen,being optionally substituted with R₇ when the carbon atom in position 2or 4 relative to this reference nitrogen is substituted with an oxo orthio group;

Z represents

either a cyclic amine attached by the nitrogen atom, of formula:

in which

-   -   A represents a C₁-C₇-alkylene group optionally substituted with        one or two groups R₈;    -   B represents a C₁-C₇-alkylene group optionally substituted with        one or two groups R₉;    -   L represents a linkage, a sulfur, oxygen or nitrogen atom; the        nitrogen atom being optionally substituted with a group R₁₀ or        R₁₁;

the carbon atoms of the cyclic amine Z being optionally substituted withone or more groups R₁₂ which may be identical to or different from oneanother; or an acyl amine, attached by the nitrogen atom, of formulaNRaRb in which Ra and Rb represent, independently of one another, ahydrogen atom or a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₆-alkylene, C₁-C₆-fluoroalkyl, hydroxyl,C₁-C₆-alkoxyl, C₃-C₇-cycloalkyl-C₁-C₆-alkylene-O—, C₁-C₆-fluoroalkoxyl,aryl or heteroaryl group, and Ra and Rb can optionally be substitutedwith one or more groups Rc which may be identical to or different fromone another;

Rc represents a halogen atom, a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₆-alkylene, C₁-C₆-fluoroalkyl, C₁-C₆-alkoxyl,C₃-C₇-cycloalkyl-C₁-C₆-alkylene-O—, C₁-C₆-fluoroalkoxyl,C₁-C₆-thioalkyl, —S(O)—C₁-C₆-alkyl, —S(O)₂—C₁-C₆-alkyl, cyano,C(O)NR₁R₂, NR₁R₂, SO₂NR₁R₂, NR₃COR₄, NR₃SO₂R₅, OC(O)NR₁R₂, NR₃COOR₅,NR₃CONR₁R₂, NR₃SO₂NR₁R₂, hydroxyl, thiol, oxo, thio,aryl-C₁-C₆-alkylene, aryl or heteroaryl group, the aryl and theheteroaryl being optionally substituted with one or more substituentsselected from a halogen, a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₆-alkylene, C₁-C₆-fluoroalkyl, C₁-C₆-alkoxyl,C₁-C₆-fluoroalkoxyl, nitro or cyano group;

R₁ and R₂ represent, independently of one another, a hydrogen atom or aC₁-C₆-alkyl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkylene,aryl-C₁-C₆-alkylene, aryl or heteroaryl group, the aryl and theheteroaryl being optionally substituted with one or more substituentsselected from a halogen, a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₆-alkylene, C₁-C₆-fluoroalkyl, C₁-C₆-alkoxyl,C₁-C₆-fluoroalkoxyl, nitro or cyano group; or R₁ and R₂ together form,with the nitrogen atom by which they are carried, an azetidinyl,pyrrolidinyl, piperidinyl, azepinyl, morpholinyl, thiomorpholinyl,piperazinyl, homopiperazinyl group, said group being optionallysubstituted with a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₆-alkylene, aryl-C₁-C₆-alkylene, aryl or heteroarylgroup, the aryl and the heteroaryl being optionally substituted with oneor more substituents selected from a halogen, a C₁-C₆-alkyl,C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkylene, C₁-C₆-fluoroalkyl,C₁-C₆-alkoxyl, C₁-C₆-fluoroalkoxyl, nitro or cyano group;

R₃ and R₄ represent, independently of one another,

a hydrogen atom or a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₆-alkylene, aryl-C₁-C₆-alkylene, aryl or heteroarylgroup, the aryl and the heteroaryl being optionally substituted with oneor more substituents selected from a halogen, a C₁-C₆-alkyl,C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkylene, C₁-C₆-fluoroalkyl,C₁-C₆-alkoxyl, C₁-C₆-fluoroalkoxyl, nitro or cyano group;

or R₃ and R₄ together form a (C₂-C₅)alkylene group;

or R₁ and R₃ together form a (C₂-C₅)alkylene group;

R₅ represents a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₆-alkylene, aryl-C₁-C₆-alkylene, aryl or heteroarylgroup, the aryl and the heteroaryl being optionally substituted with oneor more substituents selected from a halogen, a C₁-C₆-alkyl,C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkylene, C₁-C₆-fluoroalkyl,C₁-C₆-alkoxyl, C₁-C₆-fluoroalkoxyl, nitro or cyano group;

or R₃ and R₅ together form a (C₂-C₅)alkylene group;

R₆ represents a hydrogen or halogen atom or a C₁-C₆-alkyl,C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkylene, C₁-C₆-fluoroalkyl,C₁-C₆-alkoxyl, C₃-C₇-cycloalkoxyl, C₃-C₇-cycloalkyl-C₁-C₆-alkylene-O—,C₁-C₆-fluoroalkoxyl, C₁-C₆-thioalkyl, —S(O)—C₁-C₆-alkyl,—S(O)₂—C₁-C₆-alkyl, hydroxyl, thiol, oxo, thio, aryl,aryl-C₁-C₆-alkylene, heteroaryl group, the aryl and the heteroaryl beingoptionally substituted with one or more substituents selected from ahalogen, a C₁-C₆-alkyl group, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₆-alkylene, C₁-C₆-fluoroalkyl, C₁-C₆-alkoxyl,C₁-C₆-fluoroalkoxyl, nitro or cyano group;

R₇ represents a hydrogen atom, a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₆-alkylene, C₁-C₆-fluoroalkyl, C₁-C₆-alkoxyl,C₃-C₇-cycloalkoxyl, C₃-C₇-cycloalkyl-C₁-C₆-alkylene-O—,C₁-C₆-fluoroalkoxyl, aryl, aryl-C₁-C₆-alkylene or heteroaryl group, thearyl and the heteroaryl being optionally substituted with one or moresubstituents selected from a halogen, a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₆-alkylene, C₁-C₆-fluoroalkyl, C₁-C₆-alkoxyl,C₁-C₆-fluoroalkoxyl, nitro or cyano group;

R₈, R₉ and R₁₀ are defined such that:

two groups R₈ can together form a linkage or a C₁-C₆-alkylene group;

two groups R₉ can together form a linkage or a C₁-C₆-alkylene group;

R₈ and R₉ can together form a linkage or a C₁-C₆-alkylene group;

R₈ and R₁₀ can together form a linkage or a C₁-C₆-alkylene group;

R₉ and R₁₀ can together form a linkage or a C₁-C₆-alkylene group;

R₁₁ represents a hydrogen atom, a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₆-alkylene, C₁-C₆-fluoroalkyl, C₁-C₆-alkoxyl,C₃-C₇-cycloalkoxyl, C₃-C₇-cycloalkyl-C₁-C₆-alkylene-O—,C₁-C₆-fluoroalkoxyl, hydroxyl, C₁-C₆-alkyl-CO—, COOR₅, C(O)NR₁R₂,aryl-C₁-C₆-alkylene, aryl or heteroaryl group, the aryl and theheteroaryl being optionally substituted with one or more substituentsselected from a halogen, a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₆-alkylene, C₁-C₆-fluoroalkyl, C₁-C₆-alkoxyl,C₃-C₇-cycloalkoxyl, C₁-C₆-fluoroalkoxyl, nitro or cyano group;

R₁₂ represents a fluorine atom, a C₁-C₆-alkyl group optionallysubstituted with an R₁₃, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₆-alkylene, C₁-C₆-fluoroalkyl,C₁-C₆-cycloalk-1,1-diyl, C₃-C₇-heterocycloalk-1,1-diyl group optionallysubstituted on a nitrogen atom with an R₁₁, C₁-C₆-alkoxyl,C₃-C₇-cycloalkoxyl, C₃-C₇-cycloalkyl-C₁-C₆-alkylene-O—,C₁-C₆-fluoroalkoxyl, CO₂H, C(O)O—C₁-C₆-alkyl, C(O)NR₁R₂, NR₁R₂, NR₃COR₄,OC(O)NR₁R₂, NR₃COOR₅, NR₃CONR₁R₂, hydroxyl, thiol, oxo, thio,aryl-C₁-C₆-alkylene, aryl group, the aryl being optionally substitutedwith one or more substituents selected from a halogen, a C₁-C₆-alkyl,C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkylene, C₁-C₆-fluoroalkyl,C₁-C₆-alkoxyl, C₃-C₇-cycloalkoxyl, C₁-C₆-fluoroalkoxyl, nitro or cyanogroup;

R₁₃ represents a C₁-C₆-alkoxyl, C₃-C₇-cycloalkoxyl,C₃-C₇-cycloalkyl-C₁-C₆-alkylene-O—, C(O)NR₁R₂, NR₁R₂, NR₃COR₄,OC(O)NR₁R₂, NR₃COOR₅, hydroxyl group.

In the compounds of general formula (Ia), the nitrogen atom or atoms canbe in oxidized form (N-oxide).

Among the compounds of general formula (Ia), a first subgroup ofcompounds comprises compounds for which the pyrrolopyridine nucleus is apyrrolo[3,2-b]pyridine group or a pyrrolo[2,3-b]pyridine group.

Among the compounds of general formula (Ia), a second subgroup ofcompounds comprises compounds for which, if n is equal to 0, then thesubstituent or substituents X, which may be identical to or differentfrom one another, are selected from a hydrogen or halogen atom or aC₁-C₆-alkyl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkylene,C₁-C₆-fluoroalkyl, C₁-C₆-alkoxyl, C₃-C₇-cycloalkoxyl,C₃-C₇-cycloalkyl-C₁-C₆-alkylene-O—, C₁-C₆-fluoroalkoxyl, cyano,C₁-C₆-thioalkyl, —S(O)—C₁-C₆-alkyl, —S(O)₂—C₁-C₆-alkyl, SF₅, C(O)NR₁R₂,SO₂NR₁R₂, nitro, NR₁R₂, OCONR₁R₂, NR₃COR₄, NR₃CONR₁R₂, NR₃SO₂R₅,NR₃SO₂NR₁R₂ group.

Among the compounds of general formula (Ia), a third subgroup ofcompounds comprises compounds for which the substituent or substituentsX, which may be identical to or different from one another, are selectedfrom a halogen atom, more particularly a fluorine atom, or aC₁-C₆-fluoroalkyl group, more particularly trifluoromethyl.

Among the compounds of general formula (Ia), a fourth subgroup ofcompounds comprises compounds for which n is equal to 1.

Among the compounds of general formula (Ia), a fifth subgroup ofcompounds comprises compounds for which Y represents an aryl, moreparticularly a phenyl, or a heteroaryl, more particularly a pyridinyl,the aryl or the heteroaryl being optionally substituted with one ormore, more particularly by one, halogen atom(s), more particularlyfluorine atom(s).

Among the compounds of general formula (Ia), a sixth subgroup ofcompounds comprises compounds for which Z₁, Z₂, Z₃, Z₄ represent,independently of one another, a nitrogen atom or a group C(R₆), at leastone corresponding to a nitrogen atom and at least one corresponding to agroup C(R₆);

R₆ represents a hydrogen atom or a C₁-C₆-alkyl group, more particularlya methyl, or C₁-C₆-fluoroalkyl, more particularly a trifluoromethyl.

Among the compounds of general formula (Ia), a seventh subgroup ofcompounds comprises compounds for which Z represents

either a cyclic amine attached by the nitrogen atom, of formula:

in which

-   -   A represents a C₁-C₇-alkylene group;    -   B represents a C₁-C₇-alkylene group;    -   L represents a linkage;

the carbon atoms of the cyclic amine Z being optionally substituted withone or more groups R₁₂ which may be identical to or different from oneanother; R₁₂ represents a fluorine atom, a C₁-C₆-alkyl, hydroxyl group;

or an acyl amine, attached by the nitrogen atom, of formula NRaRb inwhich Ra and Rb represent, independently of one another, a hydrogen atomor a C₁-C₆-alkyl group.

Among the compounds of general formula (Ia), an eighth subgroup ofcompounds comprises compounds for which Z represents

either a pyrrolidinyl or azetidinyl group, attached by the nitrogenatom, the carbon atoms of the pyrrolidinyl group being optionallysubstituted with one or more groups R₁₂ which may be identical to ordifferent from one another; R₁₂ represents a fluorine atom, aC₁-C₆-alkyl group, more particularly methyl, or hydroxyl group;

or an acyl amine, attached by the nitrogen atom, of formula NRaRb inwhich Ra and Rb represent, independently of one another, a hydrogen atomor a C₁-C₆-alkyl group, more particularly methyl, isopropyl.

Among the compounds of general formula (Ia), a ninth subgroup ofcompounds comprises compounds of general formula (Ia) in which,simultaneously, the pyrrolopyridine nucleus and/or X and/or n and/or Yand/or Z₁, Z₂, Z₃, Z₄ and/or Z are as defined in the aforementionedsubgroups.

As non-limiting examples of substituted or unsubstituted amines Z, wemay mention methylamine, ethylamine, 2-methoxyethylamine,2-hydroxyethylamine, cyclopropylamine, hydroxylamine,2-(N,N-dimethylamino)ethylamine, dimethylamine, isopropylamine,N-ethyl-methylamine, 2,5-dimethylpyrrolidine, 3-hydroxypyrrolidine,3-ethoxypyrrolidine, 3,3-difluoropyrrolidine, 3,3-difluoroazetidine,3-hydroxyazetidine, proline, aziridine, azetidine, pyrrolidine,piperidine, azepine, morpholine, thiomorpholine, piperazine,homopiperazine, azabicyclo[3.1.0]hexanes, azabicyclo[3.2.0]heptanes,azabicyclo[3.3.0]octanes, octahydrofuropyrroles,octahydropyrrolopyrroles, octahydroindole, octahydroisoindole,octahydropyrrolopyridines, decahydroquinoline, decahydroisoquinoline,decahydronaphthyridines, octahydropyridopyrazine,azabicylo[3.1.1]heptanes, diazabicylo[2.2.1]heptanes,azabicylo[3.2.1]octanes, diazabicylo[3.2.1]octanes,azabicylo[3.3.1]nonanes.

The following definitions are used in the sense of the presentinvention:

-   -   C_(t)-C_(z) where t and z can take values from 1 to 7, a carbon        chain that can have from t to z carbon atoms, for example C₁-C₃        a carbon chain that can have from 1 to 3 carbon atoms;    -   an alkyl: a linear or branched, saturated aliphatic group. We        may mention, as examples, the methyl, ethyl, propyl, isopropyl,        butyl, isobutyl, tert-butyl, pentyl groups, etc;    -   an alkylene: a saturated, linear or branched, divalent alkyl        group, for example a C₁₋₃-alkylene group represents a divalent        carbon chain with 1 to 3 carbon atoms, linear or branched, for        example a methylene, ethylene, 1-methylethylene, propylene;    -   a cycloalkyl: a cyclic carbon group. We may mention, as        examples, the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl        groups, etc;    -   a heterocycloalkyl: a cyclic group with 3 to 7 ring members        containing 1 or 2 heteroatoms selected from O, S or N;    -   a cycloalk-1,1-diyl or a heterocycloalk-1,1-diyl: a group of the        type

where D is a cycloalkyl or heterocycloalkyl group;

-   -   a fluoroalkyl: an alkyl group in which one or more hydrogen        atoms have been substituted with a fluorine atom;    -   an alkoxyl: an —O-alkyl radical, where the alkyl group is as        defined previously;    -   a cycloalkoxyl: an —O-cycloalkyl radical, where the cycloalkyl        group is as defined previously;    -   a fluoroalkoxyl: an alkoxyl group in which one or more hydrogen        atoms have been substituted with a fluorine atom;    -   a thioalkyl: an —S-alkyl radical, where the alkyl group is as        defined previously;    -   an aryl: an aromatic cyclic group comprising between 6 and 10        carbon atoms. As examples of aryl groups, we may mention the        phenyl or naphthyl groups;    -   a heteroaryl: a mono-, bi- or tricyclic aromatic group with 5 to        14 ring members containing from 1 to 8 heteroatoms selected from        O, S or N.

As examples of monocyclic heteroaryl, we may mention the imidazolyl,pyrazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, furanyl,thiophenyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridinyl,pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl groups;

as examples of bicyclic heteroaryl, we may mention the indolyl,isoindolyl, benzofuranyl, benzothiophenyl, benzoxazolyl, benzimidazolyl,indazolyl, benzothiazolyl, isobenzofuranyl, isobenzothiazolyl,pyrrolo[2,3-c]pyridinyl, pyrrolo[2,3-b]pyridinyl,pyrrolo[3,2-b]pyridinyl, pyrrolo[3,2-c]pyridinyl, quinolinyl,isoquinolinyl, cinnolinyl, quinazolinyl or quinoxalinyl groups;

as examples of tricyclic heteroaryl, we may mention thepyrido[1,2-a]benzimidazolyl, thiazolo[1,2-a]benzimidazolyl,imidazo[1,2-a]benzimidazolyl, pyrimido[1,2-a]benzimidazolyl orpyrazino[1,2-a]benzimidazolyl groups;

-   -   a halogen atom: a fluorine, a chlorine, a bromine or an iodine;    -   “oxo” denotes “═O”;    -   “thio” denotes “═S”.

The compounds of formula (I) can have one or more asymmetric carbonatoms. They can therefore be in the form of enantiomers ordiastereoisomers. These enantiomers, diastereoisomers, as well asmixtures thereof, including the racemic mixtures, form part of theinvention.

The compounds of formula (I) can be in the form of bases or of salts ofaddition to acids. Said salts of addition form part of the invention.

These salts are advantageously prepared with pharmaceutically acceptableacids, but the salts of other acids that can be used, for example forthe purification or isolation of the compounds of formula (I), also formpart of the invention.

The compounds of general formula (I) can be in the form of hydrates orof solvates, namely in the form of associations or of combinations withone or more molecules of water or with a solvent. Said hydrates andsolvates also form part of the invention.

Among the compounds of general formula (I) according to the invention,we may notably mention the following compounds:

-   1.    N-[(6-Methylamino)pyridin-3-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   2.    N-(6-N,N-Dimethylamino-5-methylpyridin-3-yl)-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   3.    N-(6-N,N-Dimethylamino-4-methylpyridin-3-yl)-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   4.    N-(6-N,N-Dimethylamino-5-trifluoromethyl-pyridin-3-yl)-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   5.    N-[6-(Pyrrolidin-1-yl)pyridin-3-yl]-5-fluoro-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   6.    N-[6-(Pyrrolidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   7.    N-[5-(Pyrrolidin-1-yl)pyrazin-2-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   8.    N-[6-(Dimethylamino)pyridazin-3-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   9.    N-[6-(pyrrolidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-[(4-pyridyl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   10.    N-[6-(Isopropylamino)pyridin-3-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   11.    N-[6-(3-hydroxypyrrolidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   12.    N-[6-(3,3-difluoropyrrolidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   13.    N-[6-(dimethylamino)pyridin-3-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   14.    N-[6-(cis-2,5-dimethylpyrrolidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   15    N-[6-(azetidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   16    N-[6-(Pyrrolidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide-   17    N-[6-(2-(S)-carboxypyrrolidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   18    N-[6-(2-(S)-tertbutyloxycarbonylpyrrolidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   19    N-[6-(3,3-difluoroazetidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   20    N-[6-(3-hydroxyazetidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   21    N-[4-methyl-6-dimethylaminopyridin-3-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   22    N-[4-methyl-6-(pyrrolidin-1-yl)pyridin-3-yl]-6-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   23    N-[6-(3-methoxypyrrolidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   24    N-[4-methyl-6-dimethylaminopyridin-3-yl]-5-trifluoromethyl-1-[(pyridin-4-yl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   25    N-[4-methyl-6-(pyrrolidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-c    arboxamide-   26    N-[4-methyl-6-(pyrrolidin-1-yl)pyridin-3-yl]-6-trifluoromethyl-1-[(pyridin-4-yl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   27    N-[4-methyl-6-(pyrrolidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-[(pyridin-4-yl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   28    N-[4-methyl-6-(methylamino)pyridin-3-yl]-5-trifluoromethyl-1-[(pyridin-4-yl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   29    N-[4-methoxy-6-(pyrrolidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-[(pyridin-4-yl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   30    N-[6-(azetidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-[(pyridin-4-yl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   31    N-[6-(acetylamino)pyridin-3-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   32    N-[6-aminopyridin-3-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   33    N-[6-(pyrrolidin-1-yl)pyridin-3-yl]-6-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   34    N-[6-(pyrrolidin-1-yl)-4-(trifluoromethyl)pyridin-3-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   35    N-[5-fluoro-6-(dimethylamino)pyridin-3-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   35    N-[2-(dimethylamino)pyrimidin-5-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   36    N-[6-(3-azabicyclo[3.2.0]hept-3-yl)pyridin-3-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   38    N-[6-(3-azabicyclo[3.1.0]hex-3-yl)pyridin-3-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   39    N-[6-(3-azabicyclo[3.1.0]hex-3-yl)pyridin-3-yl]-5-fluoro-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   40    3-[[5-[[[1-(3-fluorobenzyl)-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-2-yl]carbonyl]amino]pyridin-2-yl]amino]propionic    acid-   41    N-[6-(3-hydroxypropylamino)pyridin-3-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   42    N-[6-(azetidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-benzyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   43    N-[6-(azetidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(2-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   44    N-[6-(azetidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(4-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   45    N-[6-(azetidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(3-trifluoromethyl)benzyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   46    N-[6-(azetidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(4-methylbenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   47    N-[6-(azetidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(3-methylbenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   48    N-[6-(azetidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(3-methoxybenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   49    N-[6-(azetidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(3-chlorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   50    N-[6-(azetidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(3-trifluoromethyloxy)benzyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   51    N-[6-(azetidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(4-methoxybenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   52    N-[6-(azetidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-[(3-chloro-5-(trifluoromethyl)]benzyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   53    N-[6-(azetidin-1-yl)pyridin-3-yl]-5-fluoro-1-benzyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   54    N-[6-(azetidin-1-yl)pyridin-3-yl]-5-fluoro-1-(2-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   55    N-[6-(azetidin-1-yl)pyridin-3-yl]-5-fluoro-1-(4-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   56    N-[6-(azetidin-1-yl)pyridin-3-yl]-5-fluoro-1-(3-trifluoromethyl)benzyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   57    N-[6-(azetidin-1-yl)pyridin-3-yl]-5-fluoro-1-(4-methylbenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   58    N-[6-(azetidin-1-yl)pyridin-3-yl]-5-fluoro-1-(3-methylbenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   59    N-[6-(azetidin-1-yl)pyridin-3-yl]-5-fluoro-1-(3-methoxybenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   60    N-[6-(azetidin-1-yl)pyridin-3-yl]-5-fluoro-1-(3-chlorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   61    N-[6-(azetidin-1-yl)pyridin-3-yl]-5-fluoro-1-(3-trifluoromethyloxy)benzyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   62    N-[6-(azetidin-1-yl)pyridin-3-yl]-5-fluoro-1-(4-methoxybenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   63    N-[6-(azetidin-1-yl)pyridin-3-yl]-5-fluoro-1-[(3-chloro-5-(trifluoromethyl)]benzyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   64    N-[6-(azetidin-1-yl)pyridin-3-yl]-6-trifluoromethyl-1-benzyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   65    N-[6-(azetidin-1-yl)pyridin-3-yl]-6-trifluoromethyl-1-(2-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   66    N-[6-(azetidin-1-yl)pyridin-3-yl]-6-trifluoromethyl-1-(4-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   67    N-[6-(azetidin-1-yl)pyridin-3-yl]-6-trifluoromethyl-1-(3-trifluoromethyl)benzyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   68    N-[6-(azetidin-1-yl)pyridin-3-yl]-6-trifluoromethyl-1-(4-methylbenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   69    N-[6-(azetidin-1-yl)pyridin-3-yl]-6-trifluoromethyl-1-(3-methylbenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   70    N-[6-(azetidin-1-yl)pyridin-3-yl]-6-trifluoromethyl-1-(3-methoxybenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   71    N-[6-(azetidin-1-yl)pyridin-3-yl]-6-trifluoromethyl-1-(3-chlorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   72    N-[6-(azetidin-1-yl)pyridin-3-yl]-6-trifluoromethyl-1-(3-trifluoromethyloxy)benzyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   73    N-[6-(azetidin-1-yl)pyridin-3-yl]-6-trifluoromethyl-1-(4-methoxybenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   74    N-[6-(azetidin-1-yl)pyridin-3-yl]-6-trifluoromethyl-1-[(3-chloro-5-(trifluoromethyl)]benzyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   75    N-[6-(azetidin-1-yl)pyridin-3-yl]-1-benzyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   76    N-[6-(azetidin-1-yl)pyridin-3-yl]-1-(2-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   77    N-[6-(azetidin-1-yl)pyridin-3-yl]-(4-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   78    N-[6-(azetidin-1-yl)pyridin-3-yl]-1-(3-trifluoromethyl)benzyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   79    N-[6-(azetidin-1-yl)pyridin-3-yl]-1-(4-methylbenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   80    N-[6-(azetidin-1-yl)pyridin-3-yl]-1-(3-methylbenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   81    N-[6-(azetidin-1-yl)pyridin-3-yl]-1-(3-methoxybenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   82    N-[6-(azetidin-1-yl)pyridin-3-yl]-1-(3-chlorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   83    N-[6-(azetidin-1-yl)pyridin-3-yl]-1-(3-trifluoromethyloxy)benzyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   84    N-[6-(azetidin-1-yl)pyridin-3-yl]-1-(4-methoxybenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   85    N-[6-(azetidin-1-yl)pyridin-3-yl]-1-[(3-chloro-5-(trifluoromethyl)]benzyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   86    N-[6-(3-hydroxyazetidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(2-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   87    N-[6-(3-hydroxyazetidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(4-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   88    N-[6-(3-hydroxyazetidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(3-trifluoromethyl)benzyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   89    N-[6-(3-hydroxyazetidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(4-methylbenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   90    N-[6-(3-hydroxyazetidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(3-methylbenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   91    N-[6-(3-hydroxyazetidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(3-methoxybenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   92    N-[6-(3-hydroxyazetidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(3-chlorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   93    N-[6-(3-hydroxyazetidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(3-trifluoromethyloxy)benzyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   94    N-[6-(3-hydroxyazetidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(4-methoxybenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   95    N-[6-(3-hydroxyazetidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-[(3-chloro-5-(trifluoromethyl)]benzyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   96    N-[6-(3-hydroxyazetidin-1-yl)pyridin-3-yl]-6-trifluoromethyl-1-benzyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   97    N-[6-(3-hydroxyazetidin-1-yl)pyridin-3-yl]-6-trifluoromethyl-1-(2-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   98    N-[6-(3-hydroxyazetidin-1-yl)pyridin-3-yl]-6-trifluoromethyl-1-(4-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

99N-[6-(3-hydroxyazetidin-1-yl)pyridin-3-yl]-6-trifluoromethyl-1-(3-trifluoromethyl)benzyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

-   100    N-[6-(3-hydroxyazetidin-1-yl)pyridin-3-yl]-6-trifluoromethyl-1-(4-methylbenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   101    N-[6-(3-hydroxyazetidin-1-yl)pyridin-3-yl]-6-trifluoromethyl-1-(3-methylbenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   102    N-[6-(3-hydroxyazetidin-1-yl)pyridin-3-yl]-6-trifluoromethyl-1-(3-methoxybenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   103    N-[6-(3-hydroxyazetidin-1-yl)pyridin-3-yl]-6-trifluoromethyl-1-(3-chlorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   104    N-[6-(3-hydroxyazetidin-1-yl)pyridin-3-yl]-6-trifluoromethyl-1-(3-trifluoromethyloxy)benzyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   105    N-[6-(3-hydroxyazetidin-1-yl)pyridin-3-yl]-6-trifluoromethyl-1-(4-methoxybenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   106    N-[6-(3-hydroxyazetidin-1-yl)pyridin-3-yl]-6-trifluoromethyl-1-[(3-chloro-5-(trifluoromethyl)]benzyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   107    N-[6-(3-hydroxyazetidin-1-yl)pyridin-3-yl]-5-fluoro-1-benzyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   108    N-[6-(3-hydroxyazetidin-1-yl)pyridin-3-yl]-5-fluoro-1-(2-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   109    N-[6-(3-hydroxyazetidin-1-yl)pyridin-3-yl]-5-fluoro-1-(4-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   110    N-[6-(3-hydroxyazetidin-1-yl)pyridin-3-yl]-5-fluoro-1-(3-trifluoromethyl)benzyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   111    N-[6-(3-hydroxyazetidin-1-yl)pyridin-3-yl]-5-fluoro-1-(4-methylbenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   112    N-[6-(3-hydroxyazetidin-1-yl)pyridin-3-yl]-5-fluoro-1-(3-methylbenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   113    N-[6-(3-hydroxyazetidin-1-yl)pyridin-3-yl]-5-fluoro-1-(3-methoxybenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   114    N-[6-(3-hydroxyazetidin-1-yl)pyridin-3-yl]-5-fluoro-1-(3-chlorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   115    N-[6-(3-hydroxyazetidin-1-yl)pyridin-3-yl]-5-fluoro-1-(3-trifluoromethyloxy)benzyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   116    N-[6-(3-hydroxyazetidin-1-yl)pyridin-3-yl]-5-fluoro-1-(4-methoxybenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   117    N-[6-(3-hydroxyazetidin-1-yl)pyridin-3-yl]-5-fluoro-1-[(3-chloro-5-(trifluoromethyl)]benzyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   118    N-[6-(3-hydroxyazetidin-1-yl)pyridin-3-yl]-1-benzyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   119    N-[6-(3-hydroxyazetidin-1-yl)pyridin-3-yl]-1-(2-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   120    N-[6-(3-hydroxyazetidin-1-yl)pyridin-3-yl]-(4-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   121    N-[6-(3-hydroxyazetidin-1-yl)pyridin-3-yl]-1-(3-trifluoromethyl)benzyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   122    N-[6-(3-hydroxyazetidin-1-yl)pyridin-3-yl]-1-(4-methylbenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   123    N-[6-(3-hydroxyazetidin-1-yl)pyridin-3-yl]-1-(3-methylbenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   124    N-[6-(3-hydroxyazetidin-1-yl)pyridin-3-yl]-1-(3-methoxybenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   125    N-[6-(3-hydroxyazetidin-1-yl)pyridin-3-yl]-1-(3-chlorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   126    N-[6-(3-hydroxyazetidin-1-yl)pyridin-3-yl]-1-(3-trifluoromethyloxy)benzyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   127    N-[6-(3-hydroxyazetidin-1-yl)pyridin-3-yl]-1-(4-methoxybenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   128    N-[6-(3-hydroxyazetidin-1-yl)pyridin-3-yl]-1-[(3-chloro-5-(trifluoromethyl)]benzyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   129    N-[6-(azetidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-benzyl-1H-pyrrolo[3,2-b]pyridine-2-carboxamide-   130    N-[6-(azetidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(2-fluorobenzyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide-   131    N-[6-(azetidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(4-fluorobenzyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide-   132    N-[6-(azetidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(3-trifluoromethyl)benzyl-1H-pyrrolo[3,2-b]pyridine-2-carboxamide-   133    N-[6-(azetidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(4-methylbenzyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide-   134    N-[6-(azetidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(3-methylbenzyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide-   135    N-[6-(azetidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(3-methoxybenzyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide-   136    N-[6-(azetidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(3-chlorobenzyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide-   137    N-[6-(azetidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(3-trifluoromethyloxy)benzyl-1H-pyrrolo[3,2-b]pyridine-2-carboxamide-   138    N-[6-(azetidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(4-methoxybenzyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide-   139    N-[6-(azetidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-[(3-chloro-5-(trifluoromethyl)]benzyl-1H-pyrrolo[3,2-b]pyridine-2-carboxamide-   140    N-[6-(3-hydroxyazetidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-benzyl-1H-pyrrolo[3,2-b]pyridine-2-carboxamide-   141    N-[6-(3-hydroxyazetidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(2-fluorobenzyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide-   142    N-[6-(3-hydroxyazetidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(4-fluorobenzyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide-   143    N-[6-(3-hydroxyazetidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(3-trifluoromethyl)benzyl-1H-pyrrolo[3,2-b]pyridine-2-carboxamide-   144    N-[6-(3-hydroxyazetidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(4-methylbenzyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide-   145    N-[6-(3-hydroxyazetidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(3-methylbenzyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide-   146    N-[6-(3-hydroxyazetidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(3-methoxybenzyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide-   147    N-[6-(3-hydroxyazetidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(3-chlorobenzyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide-   148    N-[6-(3-hydroxyazetidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(3-trifluoromethyloxy)benzyl-1H-pyrrolo[3,2-b]pyridine-2-carboxamide-   149    N-[6-(azetidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(4-methoxybenzyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide-   150    N-[6-(3-hydroxyazetidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-[(3-chloro-5-(trifluoromethyl)]benzyl-1H-pyrrolo[3,2-b]pyridine-2-carboxamide-   151    N-[6-(azetidin-1-yl)pyridin-3-yl]-1-benzyl-1H-pyrrolo[2,3-c]pyridine-2-carboxamide-   152    N-[6-(azetidin-1-yl)pyridin-3-yl]-1-(2-fluorobenzyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide-   153    N-[6-(azetidin-1-yl)pyridin-3-yl]-(4-fluorobenzyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide-   154    N-[6-(azetidin-1-yl)pyridin-3-yl]-1-(3-trifluoromethyl)benzyl-1H-pyrrolo[2,3-c]pyridine-2-carboxamide-   155    N-[6-(azetidin-1-yl)pyridin-3-yl]-1-(4-methylbenzyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide-   156    N-[6-(azetidin-1-yl)pyridin-3-yl]-1-(3-methylbenzyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide-   157    N-[6-(azetidin-1-yl)pyridin-3-yl]-1-(3-methoxybenzyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide-   158    N-[6-(azetidin-1-yl)pyridin-3-yl]-1-(3-chlorobenzyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide-   159    N-[6-(azetidin-1-yl)pyridin-3-yl]-1-(3-trifluoromethyloxy)benzyl-1H-pyrrolo[2,3-c]pyridine-2-carboxamide-   160    N-[6-(azetidin-1-yl)pyridin-3-yl]-1-[(3-chloro-5-(trifluoromethyl)]benzyl-1H-pyrrolo[2,3-c]pyridine-2-carboxamide-   161    N-[6-(3-hydroxyazetidin-1-yl)pyridin-3-yl]-1-benzyl-1H-pyrrolo[2,3-c]pyridine-2-carboxamide-   162    N-[6-(3-hydroxyazetidin-1-yl)pyridin-3-yl]-1-(2-fluorobenzyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide-   163    N-[6-(3-hydroxyazetidin-1-yl)pyridin-3-yl]-(4-fluorobenzyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide-   164    N-[6-(3-hydroxyazetidin-1-yl)pyridin-3-yl]-1-(3-trifluoromethyl)benzyl-1H-pyrrolo[2,3-d]pyridine-2-carboxamide-   165    N-[6-(3-hydroxyazetidin-1-yl)pyridin-3-yl]-1-(4-methylbenzyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide-   166    N-[6-(3-hydroxyazetidin-1-yl)pyridin-3-yl]-1-(3-methylbenzyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide-   167    N-[6-(3-hydroxyazetidin-1-yl)pyridin-3-yl]-1-(3-methoxybenzyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide-   168    N-[6-(3-hydroxyazetidin-1-yl)pyridin-3-yl]-1-(3-chlorobenzyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide-   169    N-[6-(3-hydroxyazetidin-1-yl)pyridin-3-yl]-1-(3-trifluoromethyloxy)benzyl-1H-pyrrolo[2,3-d]pyridine-2-carboxamide-   170    N-[6-(3-hydroxyazetidin-1-yl)pyridin-3-yl]-1-[(3-chloro-5-(trifluoromethyl)]benzyl-1H-pyrrolo[2,3-c]pyridine-2-carboxamide-   171    3-[[5-[[[1-(3-fluorobenzyl)-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-2-yl]carbonyl]amino]pyridin-2-yl]amino]ethyl    propionate-   172    N-[6-(3-methoxyazetidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   173    N-[6-[3-(cyclopropyl)methyloxy)azetidin-1-yl]pyridin-3-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide    Among the compounds of general formula (I) according to the    invention, we may also mention the following compounds:-   1.    N-[(6-Methylamino)pyridin-3-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   2.    N-(6-N,N-dimethylamino-5-methylpyridin-3-yl)-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   3.    N-(6-N,N-dimethylamino-4-methylpyridin-3-yl)-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   4. N-(6-N,N-dim    ethylamino-5-trifluoromethyl-pyridin-3-yl)-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   5.    N-[6-(Pyrrolidin-1-yl)pyridin-3-yl]-5-fluoro-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   6.    N-[6-(Pyrrolidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   7.    N-[5-(Pyrrolidin-1-yl)pyrazin-2-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   8.    N-[6-(Dimethylamino)pyridazin-3-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   9.    N-[6-(pyrrolidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-[(4-pyridyl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

10.N[6-(Isopropylamino)pyridin-3-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

-   11.    N-[6-(3-hydroxypyrrolidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   12.    N-[6-(3,3-difluoropyrrolidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   13.    N-[6-(dimethylamino)pyridin-3-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   14.    N-[6-(cis-2,5-dimethylpyrrolidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   15.    N-[6-(azetidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   16.    N-[6-(Pyrrolidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide-   17    N-[6-(2-(S)-carboxypyrrolidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   18    N-[6-(2-(S)-tertbutyloxycarbonylpyrrolidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   19    N-[6-(3,3-difluoroazetidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   20    N-[6-(3-hydroxyazetidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   21    N-[4-methyl-6-dimethylaminopyridin-3-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   22.    N-[4-methyl-6-(pyrrolidin-1-yl)pyridin-3-yl]-6-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   23.    N-[6-(3-methoxypyrrolidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   24.    N-[4-methyl-6-dimethylaminopyridin-3-yl]-5-trifluoromethyl-1-[(pyridin-4-yl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   25.    N-[4-methyl-6-(pyrrolidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   26.    N-[4-methyl-6-(pyrrolidin-1-yl)pyridin-3-yl]-6-trifluoromethyl-1-[(pyridin-4-yl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   27.    N-[4-methyl-6-(pyrrolidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-[(pyridin-4-yl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   28.    N-[4-methyl-6-(methylamino)pyridin-3-yl]-5-trifluoromethyl-1-[(pyridin-4-yl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   29.    N-[4-methoxy-6-(pyrrolidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-[(pyridin-4-yl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   30.    N-[6-(azetidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-[(pyridin-4-yl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   31.    N-[6-(acetylamino)pyridin-3-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   32.    N-[6-aminopyridin-3-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   33.    N-[6-(pyrrolidin-1-yl)pyridin-3-yl]-6-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   34.    N-[6-(pyrrolidin-1-yl)-4-(trifluoromethyl)pyridin-3-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   35.    N-[5-fluoro-6-(dimethylamino)pyridin-3-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   36.    N-[2-(dimethylamino)pyrimidin-5-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   37.    N-[6-(3-azabicyclo[3.2.0]hept-3-yl)pyridin-3-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   38.    N-[6-(3-azabicyclo[3.1.0]hex-3-yl)pyridin-3-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   39.    N-[6-(3-azabicyclo[3.1.0]hex-3-yl)pyridin-3-yl]-5-fluoro-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   40.    3-[[5-[[[1-(3-fluorobenzyl)-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-2-yl]carbonyl]amino]pyridin-2-yl]amino]propionic    acid-   41.    N-[6-(3-hydroxypropylamino)pyridin-3-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   43.    N-[6-(azetidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(2-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   44.    N-[6-(azetidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(4-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   45.    N-[6-(azetidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(3-trifluoromethyl)benzyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   46.    N-[6-(azetidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(4-methylbenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   48.    N-[6-(azetidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(3-methoxybenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   49.    N-[6-(azetidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(3-chlorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   50.    N-[6-(azetidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(3-trifluoromethyloxy)benzyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   51.    N-[6-(azetidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(4-methoxybenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   62.    N-[6-(azetidin-1-yl)pyridin-3-yl]-5-fluoro-1-(4-methoxybenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   67.    N-[6-(azetidin-1-yl)pyridin-3-yl]-6-trifluoromethyl-1-(3-trifluoromethyl)benzyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   68.    N-[6-(azetidin-1-yl)pyridin-3-yl]-6-trifluoromethyl-1-(4-methylbenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   71.    N-[6-(azetidin-1-yl)pyridin-3-yl]-6-trifluoromethyl-1-(3-chlorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   75.    N-[6-(azetidin-1-yl)pyridin-3-yl]-1-benzyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   78.    N-[6-(azetidin-1-yl)pyridin-3-yl]-1-(3-trifluoromethyl)benzyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   81.    N-[6-(azetidin-1-yl)pyridin-3-yl]-1-(3-methoxybenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   84.    N-[6-(azetidin-1-yl)pyridin-3-yl]-1-(4-methoxybenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   115.    N-[6-(3-hydroxyazetidin-1-yl)pyridin-3-yl]-5-fluoro-1-(3-trifluoromethyloxy)benzyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   116.    N-[6-(3-hydroxyazetidin-1-yl)pyridin-3-yl]-5-fluoro-1-(4-methoxybenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   117.    N-[6-(3-hydroxyazetidin-1-yl)pyridin-3-yl]-5-fluoro-1-[(3-chloro-5-(trifluoromethyl)]benzyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   124.    N-[6-(3-hydroxyazetidin-1-yl)pyridin-3-yl]-1-(3-methoxybenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   125.    N-[6-(3-hydroxyazetidin-1-yl)pyridin-3-yl]-1-(3-chlorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide-   129.    N-[6-(azetidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-benzyl-1H-pyrrolo[3,2-b]pyridine-2-carboxamide-   130.    N-[6-(azetidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(2-fluorobenzyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide-   131.    N-[6-(azetidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(4-fluorobenzyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide-   134.    N-[6-(azetidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(3-methylbenzyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide-   135.    N-[6-(azetidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(3-methoxybenzyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide-   138.    N-[6-(azetidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(4-methoxybenzyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide-   164.    N-[6-(3-hydroxyazetidin-1-yl)pyridin-3-yl]-1-(3-trifluoromethyl)benzyl-1H-pyrrolo[2,3-c]pyridine-2-carboxamide-   165.    N-[6-(3-hydroxyazetidin-1-yl)pyridin-3-yl]-1-(4-methylbenzyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide

Hereinafter, by “leaving group”, we mean a group that can easily becleaved from a molecule by rupture of a heterolytic bond, with departureof an electron pair. This group can thus be replaced easily by anothergroup during a substitution reaction, for example. Said leaving groupsare, for example, the halogens or an activated hydroxyl group such as amethanesulfonate, benzenesulfonate, p-toluenesulfonate, triflate,acetate, etc. Examples of leaving groups as well as references for theirpreparation are given in “Advances in Organic Chemistry”, J. March,5^(th) Edition, Wiley Interscience, 2001.

In accordance with the invention, the compounds of general formula (I)can be prepared according to the method shown below in Scheme 1.

According to Scheme 1, the compounds of general formula (IV) can beobtained by reaction of a compound of general formula (II) in which X isas defined in general formula (I) and B represents a C₁-C₆-alkoxylgroup, with a compound of general formula (III), in which Y and n are asdefined in general formula (I) and GP represents a leaving group or GPrepresents a hydroxyl group.

In Scheme 1, the compounds of general formula (II), when their method ofpreparation is not described, are commercially available, described inthe literature or prepared by analogy with numerous methods described inthe literature (P. Roy et al. Synthesis 2005, 16, 2751-2757; N. Lahanceet al. Synthesis 2005, 15, 2571-2577; C. Barberis et al. TetrahedronLett 2005, 46(51), 8877-8880; T. Lomberget Synlett 2005, 13, 2080-2082;1909; M. Nazare et al. Angew Chem Int Ed 2004, 43(34), 4526-4528; P. M.Fresneda et al. Tetrahedron Lett 2000, 41(24), 4777-4780).

When the compound of general formula (III) is defined such that n isequal to 1, 2 or 3 and GP represents a leaving group such as a chlorine,bromine or iodine atom, the reaction can be carried out in the presenceof a base such as sodium hydride or potassium carbonate, in a polarsolvent such as dimethylformamide, dimethylsulfoxide or acetone (n=1:Kolasa T., Bioorg. Med. Chem. 1997, 5 (3) 507, n=2: Abramovitch R.,Synth. Commun., 1995, 25 (1), 1).

When the compound of general formula (III) is defined such that n isequal to 1, 2 or 3 and GP represents a hydroxyl group, the compounds ofgeneral formula (IV) can be obtained by reaction of the compound ofgeneral formula (II) with a compound of general formula (III) in thepresence of a phosphine such as, for example, triphenylphosphine and areagent such as, for example, diethyl azodicarboxylate in solution in asolvent such as dichloromethane or tetrahydrofuran (O. Mitsunobu,Synthesis, 1981, 1-28). Similarly, the compounds of general formula (IV)can be obtained by reaction of the compound of general formula (II) witha compound of general formula (III) in the presence of a phosphinesupported on a resin and a reagent such as, for example, diisopropylazodicarboxylate in solution in a solvent such as dichloromethane ortetrahydrofuran.

When the compound of general formula (III) is defined such that n isequal to 0 and GP represents a leaving group such as a chlorine, bromineor iodine atom, the reaction can be carried out by application andadaptation of the methods described by S. L. Buchwald et al. (J. Am.Chem. Soc., 2001, 123, 7727 and 2002, 124, 11684), preferably under aninert atmosphere in a basic medium, for example in the presence ofpotassium triphosphate, in the presence of a copper salt such as copperiodide, optionally in the presence of an additive such asN,N′-dimethylcyclohexane-1,2-diamine, the whole in an organic solventsuch as toluene.

The compound of general formula (IV), for which B represents aC₁-C₆-alkoxy group, can be converted to a compound of general formula(IV), where B represents a hydroxyl group, by the action of a base suchas sodium hydroxide or potassium hydroxide in solution in a solvent suchas ethanol. The compound of general formula (IV), where B represents ahydroxyl group, can then be converted to a compound of general formula(IV), where B represents a chlorine atom, by the action of achlorinating agent such as thionyl chloride in a solvent such asdichloromethane.

The compound of general formula (VI) can then be obtained, for example,by reaction of a compound of general formula (IV) where B is a chlorineatom, as obtained above, with an amine of general formula (V), in whichZ₁, Z₂, Z₃, Z₄ are as defined in general formula (I) and W correspondsto a halogen such as a chlorine atom, in a solvent such asdichloroethane, toluene or tetrahydrofuran.

The compound of general formula (VI) can also be obtained by reaction ofa compound of general formula (IV) where B is a hydroxyl group, asobtained above, with an amine of general formula (V), in which Z₁, Z₂,Z₃, Z₄ are as defined in general formula (I) and W corresponds to ahalogen atom such as a chlorine atom, in the presence of a couplingagent such as diethyl cyanophosphonate or N-(3-dimethylaminopropyl)-N′ethylcarbodiimide, optionally in the presence of a base such astriethylamine, in a solvent such as dimethylformamide.

The compound of general formula (I) can be obtained, for example, byreaction of a compound of general formula (IV) where B is a chlorineatom, as obtained above, with an amine of general formula (V), in whichW═Z and Z, Z₁, Z₂, Z₃, Z₄ are as defined in general formula (I), in asolvent such as dichloroethane, toluene or tetrahydrofuran.

The compound of general formula (I) can also be obtained by reaction ofa compound of general formula (IV) where B is a hydroxyl group, asobtained above, with an amine of general formula (V), in which W═Z andZ, Z₁, Z₂, Z₃, Z₄ are as defined in general formula (I), in the presenceof a coupling agent such as diethylcyanophosphonate orN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide, and optionally in thepresence of a base such as triethylamine, in a solvent such asdimethylformamide.

The compound of general formula (I) can also be obtained by reaction ofa compound of general formula (VI) in the presence of an amine offormula Z—H, in which Z is as defined in general formula (I), withoutsolvent or in a solvent such as N-methylpyrrolidone, or alternatively byapplication and adaptation of the methods described by S. L. Buchwald etal. (J. Am. Chem. Soc., 2001, 123, 7727 and 2002, 124, 11684),preferably under an inert atmosphere in a basic medium, for example inthe presence of potassium triphosphate, in the presence of a copper saltsuch as copper iodide, optionally in the presence of an additive such asN,N′-dimethylcyclohexane-1,2-diamine, the whole in an organic solventsuch as toluene, or alternatively by application and adaptation of themethods described by Hartwig et al. (Angewandte Chemie, 2005, 44,1371-1375), for example in the presence of a base and catalytic amountsof a palladium-based catalyst, such as palladium diacetate, and aphosphine.

The compounds of general formulae (I), (II) and (IV), in which Xrepresents a cyano or an aryl group, can be obtained by a couplingreaction, catalyzed by a metal such as palladium, carried out on thecorresponding compounds of general formulae (I), (II) and (IV), in whichX represents a leaving group, for example a bromine, according tomethods that are described in the literature or that are known by aperson skilled in the art.

The compounds of general formulae (I), (II) and (IV), in which Xrepresents a group C(O)NR₁R₂, can be obtained from the correspondingcompounds of general formulae (I), (II) and (IV), in which X representsa cyano group, according to methods that are described in the literatureor are known by a person skilled in the art.

The compounds of general formulae (I), (II), (IV) and (VI) in which Xrepresents a —S(O)-alkyl or —S(O)₂-alkyl group can be obtained byoxidation of the corresponding compounds of general formulae (I), (II),(IV) and (VI), in which X represents a C₁-C₆-thioalkyl group, accordingto methods that are described in the literature or that are known by aperson skilled in the art.

The compounds of general formulae (I), (II), (IV) and (VI) in which Xrepresents a group NR₁R₂, NR₃COR₄ or NR₃SO₂R₅, can be obtained from thecorresponding compounds of general formulae (I), (II), (IV) and (VI), inwhich X represents a nitro group, for example by reduction, thenacylation or sulfonylation, according to methods that are described inthe literature or that are known by a person skilled in the art.

The compounds of general formulae (I), (II) and (IV), in which Xrepresents a group NR₁R₂, NR₃COR₄ or NR₃SO₂R₅, can be obtained from thecorresponding compounds of general formulae (I), (II) and (IV), in whichX represents for example a bromine atom, by a coupling reactionrespectively with an amine, an amide or a sulfonamide in the presence ofa base, a phosphine and a palladium-based catalyst, according to methodsthat are described in the literature or that are known by a personskilled in the art.

The compounds of general formulae (I), (II) and (IV), in which Xrepresents a group SO₂NR₁R₂, can be obtained by a method similar to thatdescribed in Pharmazie 1990, 45, 346, or according to methods that aredescribed in the literature or that are known by a person skilled in theart.

The compounds of general formula (I) in which Z represents an acyclicamine NRaRb corresponding to a group NH₂ can be obtained, according toconditions known by a person skilled in the art and described in theliterature (Greene, Wuts, Protective groups in organic synthesis,Wiley-Interscience) from precursors of general formula (I) whereNRaRb=NH-GP, GP corresponding to a protecting group such as an acetyl orterbutoxycarbonyl group.

The compounds of general formula (I) having a group CO₂H can beobtained, according to conditions known by a person skilled in the artand described in the literature (Greene, Wuts, Protective groups inorganic synthesis, Wiley-Interscience) from precursors of generalformula (I) having a group CO₂GP, GP corresponding to a protecting groupof carboxylic acid such as a methyl or tertbutyl group.

The compounds of general formula (I) having a group CH₂OH can beobtained, according to conditions known by a person skilled in the art,from compounds of general formula (I) having a group CO₂alkyl, forexample, by reaction in the presence of a reducing agent such as sodiumborohydride in a solvent such as tetrahydrofuran.

The compounds of general formula (III) are commercially available,described in the literature (Carling R. W. et al. J. Med. Chem. 2004(47), 1807-1822 or Russel M. G. N. et al. J. Med. Chem. 2005 (48),1367-1383) or can be obtained using methods known by a person skilled inthe art.

The compounds of general formula (V) and the other reactants, when theirmethod of preparation is not described, are commercially available orare described in the literature (WO2005028452, WO2002048152,WO2006040522, WO2004052869, WO2004062665, WO2005035526, WO2004110986,Heterocycles 1977, 6(12), 1999-2004, for example).

The invention, according to another of its aspects, also relates to thecompounds of formulae (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (Vg) and (Vh).These compounds can be used as synthetic intermediates for thepreparation of the compounds of formula (I).

The amines of formulae (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (Vg) and (Vh)can be prepared, for example, according to the method described inexample 12.1, by aromatic nucleophilic substitution of a 6-halopyridineprecursor, optionally substituted (Vd: by a 4-methoxy group, Vg: by a4-trifluoromethyl group), with an amine, such as pyrrolidine, forexample in a solvent such as ethanol.

The amine (Vb) can be prepared for example according to the methoddescribed in Example 7 by heating a solution of commercial2-amino-5-bromopyrazine in pyrrolidine. Access to the amines Va-h mayalso necessitate the reduction of a nitro group, for example bycatalytic hydrogenation in the presence of a catalyst such as palladiumon charcoal, or by all other methods known by a person skilled in theart, for reduction of a nitro group to amine. Access to the amines Va-hmay also necessitate, as in the case of the amine (Vg) described inExample 17, the introduction of an amine group by rearrangement of acarboxylic acid group according to the Curtius rearrangement or by allother methods known by a person skilled in the art.

The amines of formulae (Va), (Vb), (Vc), (Vd), (Ve), (Vf), (Vg) and (Vh)have been prepared as a base or a salt of addition to an acid.

Table 1 presents the ¹H NMR data for these amines.

TABLE 1 No. ¹H NMR, δ (ppm): Va In DMSO D₆, δ (ppm): 7.62 (d, 1H); 6.95(d, 1H); 6.49 (d, 1H); 4.42 (broadened peak, 2H); 3.52 (d, 2H); 2.98 (m,4H); 2.21 (m, 2H); 1.72 (m, 2H). Vb In DMSO D₆, δ (ppm): 7.5 (d, 1H);7.32 (d, 1H); 5.15 (s, 2H); 3.25 (m, 4H); 1.88 (m, 4H). Vc In DMSO D₆, δ(ppm): 7.57 (d, 1H); 6.92 (dxd, 1H); 6.2 (d, 1H); 4.46 (broadened peak,2H); 3.78 (m, 4H); 2.25 (quint., 2H). Vd In DMSO D₆, δ (ppm): 7.16 (s,1H); 6.61 (s, 1H); 4.52 (broadened peak, 2H); 3.71 (s, 3H); 3.29 (m,4H); 1.81 (m, 4H). Ve In DMSO D₆, δ (ppm): 7.58 (s, 1H); 6.91 (d, 1H);6.22 (d, 1H); 5.48 (broadened peak, 1H); 4.48 (broadened peak, 3H); 3.98(m, 2H); 3.49 (m, 2H); Vf In DMSO D₆, δ (ppm): 7.55 (s, 1H); 6.99 (d,1H); 6.25 (d, 1H); 4.32 (broadened peak, 2H); 3.51 (d, 2H); 3.11 (m,2H); 1.6 (m, 2H); 0.66 (m, 1H); 0.2 (m, 1H). Vg In DMSO D₆, δ (ppm):7.92 (s, 1H); 7.49 (broadened (HCl 1:1) peak, 2H); 7.1 (s, 1H); 3.52 (m,4H); 2 (m, 4H). Vh In DMSO D₆, δ (ppm): 7.6 (s, 1H); 6.96 (dxd, 1H); 6.4(d, 1H); 4.67 (s, 2H); 4.2 (t, 4H).

The following examples describe the preparation of some compoundsaccording to the invention. These examples are not limiting and merelyillustrate the present invention. The numbers of the example compoundsrefer to those given in Table 1. Elemental microanalyses, LC-MS analyses(liquid chromatography coupled to mass spectrometry) IR spectra or NMRspectra confirm the structures of the compounds obtained.

Example 1 Compound No. 1 in Table 2N-[(6-Methylamino)pyridin-3-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide1.1. 5-Trifluoromethyl-1H-pyrrolo[2,3-b]pyridine-2-ethyl carboxylate

Put 0.3 g (1.3 mmol) of5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (AngewChem Int Ed 2004, 43(34), 4526-4528) and 50 mL of ethanol in a 100-mLflask equipped with a magnetic stirrer. Add, to this solution, 0.5 mL ofconcentrated sulfuric acid. The reaction mixture is then refluxed for 18hours. The cooled solution is concentrated to dryness at reducedpressure. The residue is taken up in dichloromethane (100 mL), theorganic phase is washed successively with a normal aqueous solution ofsodium hydroxide (30 mL), with water (20 mL) and then with a saturatedaqueous solution of sodium chloride. It is dried over sodium sulfate andthen concentrated at reduced pressure. 0.29 g (1.12 mmol) of theexpected product is isolated in the form of a yellow powder.

¹H NMR (DMSO D₆), δ (ppm): 12.95 (s, NH); 8.8 (d, 1H); 8.6 (d, 1H); 7.3(s, 1H); 4.4 (q, 2H); 1.35 (t, 3H).

1.25-Trifluoromethyl-1-[(3-fluorophenyl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-ethylcarboxylate

To a solution of 0.3 g (1.16 mmol) of product obtained in Stage 1.1, in20 mL of dry tetrahydrofuran, held under an inert atmosphere, addsuccessively, while stirring, 0.23 g (1.74 mmol) of 3-fluorobenzylalcohol and then 0.46 g (1.74 mmol) of triphenylphosphine. Then add,dropwise, 0.31 g (1.74 mmol) of diethyl azodicarboxylate. The reactionmixture is then stirred for 20 h at room temperature and is thenconcentrated at reduced pressure. The resultant oil is purified bychromatography on a column of silica gel, eluting with a mixture ofheptane and ethyl acetate. 0.34 g (0.93 mmol) of the expected product isisolated.

¹H NMR (DMSO D₆), δ (ppm): 8.9 (d, 1H); 8.7 (d, 1H); 7.5 (s, 1H);7.4-6.95 (m, 2H); 6.85 (m, 2H); 5.9 (s, 2H); 4.3 (q, 2H), 1.3 (t, 3H).

1.35-Trifluoromethyl-1-[(3-fluorophenyl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxylicacid

A solution of 3.15 g (8.6 mmol) of5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-ethylcarboxylate obtained in Stage 1.2 in 100 mL of ethanol and of 26 mL of2N sodium hydroxide is stirred for four hours under reflux. After thistime, the reaction mixture is concentrated at reduced pressure, and thenis taken up in 40 mL of water. The reaction mixture is acidified to pH 3by successive additions of 1N hydrochloric acid. The precipitate iscollected by filtration, washed with water and then dried at reducedpressure. Thus, 2.9 g of the expected product is isolated in the form ofa white powder, which is used as it is in the next stage.

¹H NMR (DMSO D₆), δ (ppm): 13.5 (broadened peak, 1H); 8.81 (d, 1H); 8.63(d, 1H); 7.47 (s, 1H); 7.3 (m, 1H); 7.1-6.8 (m, 3H); 5.94 (s, 2H).

1.4N-[(6-Methylamino)pyridin-3-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide(Compound No. 1 in Table 2)

109 mg (0.89 mmol) of 2-(methylamino)-5-aminopyridine (J. Med. Chem.1994 (37) 18-25) is added to a solution, stirred at 20° C., of 0.2 g(0.59 mmol) of the compound prepared in Stage 1.3, 113 mg (0.59 mmol) ofN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDAC) and79 mg (0.59 mmol) of 1-hydroxy-benzotriazole (HOBT) in 50 mL of DMF. Thereaction mixture is stirred for 14 hours at 20° C. and is then pouredinto 50 mL of water. The mixture is then extracted with 3×30 mL of ethylacetate. The combined organic phases are washed twice with 20 mL ofwater, dried over sodium sulfate and then concentrated at reducedpressure. The product obtained is purified by chromatography on a silicacolumn, eluting with a mixture of dichloromethane and methanol. Thus, 54mg of the expected product is isolated.

m.p.=252-254° C.

¹H NMR (DMSO D₆), δ (ppm): 10.35 (s, 1H); 8.79 (d, 1H); 8.7 (d, 1H);8.21 (d, 1H); 7.65 (dxd, 1H); 7.49 (s, 1H); 7.27 (m, 1H); 7.1-6.85 (m,3H); 6.4 (m, 2H); 5.93 (s, 2H); 2.77 (d, 3H).

Example 2 Compound No. 2 in Table 2N-(6-N,N-Dimethylamino-5-methyl-pyridin-3-yl)-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamidehydrochloride (1:1) 2.1 6-N,N-Dimethylamino-5-methyl-3-nitropyridine

0.95 g (5.5 mmol) of 6-chloro-5-methyl-3-nitropyridine, 5 mL (39.8 mmol)of an aqueous solution of dimethylamine at 40% and 2 mL of ethanol areput in a Schlenk tube, equipped with a magnetized bar. The tube isclosed and the reaction mixture is stirred at 120° C. for 15 hours.After this time, the tube is cooled, the reaction mixture isconcentrated at reduced pressure, and is then taken up in 50 mL ofwater. The resultant mixture is extracted twice with 30 mL ofdichloromethane. The combined organic phases are washed with 50 mL of asaturated aqueous solution of sodium chloride, dried over sodium sulfateand concentrated at reduced pressure. We thus obtain 0.95 g of theexpected product in the form of a yellow solid, which will be used as itis in the rest of the synthesis.

¹H NMR (CDCl₃), δ (ppm): 8.84 (d, 1H); 7.98 (d, 1H); 3.1 (s, 6H); 2.3(s, 3H).

2.2 6-N,N-Dimethylamino-5-methyl-3-aminopyridine

A suspension of 0.94 g (5.2 mmol) of the product obtained in Stage 2.1,0.5 mL (10.4 mmol) of hydrazine monohydrate and 0.4 g of Raney Nickel in40 mL of ethanol is stirred for three hours at 20° C. The insolublematter is removed by filtration on a Celite pad, and the filtrate isconcentrated at reduced pressure. We thus obtain 0.8 g of the expectedproduct, which will be used as it is in the rest of the synthesis.

¹H NMR (CDCl₃), δ (ppm): 7.61 (d, 1H); 6.78 (d, 1H); 3.4-3.1 (broadenedpeak, 2H); 2.65 (s, 6H); 2.19 (s, 3H).

2.3N-(6-N,N-Dimethylamino-5-methyl-pyridin-3-yl)-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamidehydrochloride (1:1) (compound No. 2 in Table 2)

Compound No. 2 was prepared by a method similar to that described inStage 1.4, by reacting 0.17 g (1.11 mmol) of the amine obtained in Stage2.2 with 0.25 g (0.74 mmol) of the acid obtained in Stage 1.3. Theproduct obtained is taken up in 5 mL of 0.1N hydrochloric acid inisopropanol and 5 mL of dichloromethane. The solution is concentrated atreduced pressure, thus isolating 0.23 g of the expected product in theform of hydrochloride.

m.p.=252-257° C.; Hydrochloride (1:1)

¹H NMR (DMSO D₆), δ (ppm): 10.88 (s, 1H); 8.8 (s, 1H); 8.71 (s, 1H);8.42 (d, 1H); 8.02 (d, 1H); 7.63 (s, 1H); 7.28 (m, 1H); 7.1-6.85 (m,3H); 5.93 (s, 2H); 2.97 (s, 6H); 2.32 (s, 3H).

Example 3 Compound No. 3 in Table 2N-(6-N,N-Dimethylamino-4-methyl-pyridin-3-yl)-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamidehydrochloride (1:1)

Compound No. 3 was prepared by a method similar to that described inStage 1.4, by reacting 0.17 g (1.11 mmol) of6-N,N-dimethylamino-4-methyl-3-aminopyridine (WO2004062665) with 0.25 g(0.74 mmol) of the acid obtained in Stage 1.3. The product obtained istaken up in 3.8 mL of 0.1N hydrochloric acid in isopropanol and 2 mL ofdichloromethane. After 15 hours at 20° C., the precipitate is collectedby filtration and rinsed with 50 mL of ethyl ether, and is then dried atreduced pressure. 0.15 g of the expected product is thus isolated in theform of hydrochloride.

m.p.=242-247° C.; Hydrochloride (1:1)

¹H NMR (DMSO D₆), δ (ppm): 10.31 (s, 1H); 8.8 (s, 1H); 8.73 (s, 1H);7.91 (s, 1H); 7.6 (s, 1H); 7.3 (m, 1H); 7.1-6.8 (m, 4H); 5.91 (s, 2H);3.16 (s, 6H); 2.18 (s, 3H).

Example 4 Compound No. 4 in Table 2N-(6-N,N-Dimethylamino-5-trifluoromethyl-pyridin-3-yl)-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamidehydrochloride (1:1)

Compound No. 4 was prepared by a method similar to that described inStage 1.4, by reacting 0.15 g (0.74 mmol) of6-N,N-dimethylamino-5-trifluoromethyl-3-aminopyridine (WO2004110986)with 0.25 g (0.74 mmol) of the acid obtained in Stage 1.3. The productobtained is taken up in 3.8 mL of 0.1N hydrochloric acid in isopropanoland 2 mL of dichloromethane. The solution is concentrated at reducedpressure, thus isolating 0.28 g of the expected product in the form ofhydrochloride.

m.p.=213-218° C.; Hydrochloride (1:1)

¹H NMR (DMSO D₆), δ (ppm): 10.81 (s, 1H); 8.75 (m, 3H); 8.31 (d, 1H);7.61 (s, 1H); 7.3 (m, 1H); 7.1-6.85 (m, 3H); 5.94 (s, 2H); 2.88 (s, 6H).

Example 5 Compound No. 5 in Table 2N-[6-(Pyrrolidin-1-yl)pyridin-3-yl]-5-fluoro-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide5.1 2-Amino-3-iodo-5-fluoropyridine

5 g (44.6 mmol) of 2-amino-5-fluoropyridine, 13.9 g (44.6 mmol) ofsilver sulfate and 400 mL of ethanol are put in a 500-mL two-neckedflask equipped with a magnetic stirrer. Then 11.31 g (44.6 mmol) ofiodine powder is added, in small portions. It is stirred at roomtemperature for 24 hours. The insoluble matter is removed by filtrationand is washed with ethanol, and the filtrate is concentrated at reducedpressure. The residue thus obtained is taken up in a mixture of ethylacetate (200 mL) and sodium carbonate solution (200 mL). Afterseparation, the organic phase is washed successively with a 25% aqueoussolution of sodium thiosulfate then with a saturated aqueous solution ofsodium chloride, then it is dried over sodium sulfate and concentratedat reduced pressure. The resultant solid is purified by chromatographyon a silica column, eluting with a mixture of n-heptane and ethylacetate. We obtain 2.67 g (11.22 mmol) of the expected product.

¹H NMR (DMSO D₆), δ (ppm): 7.95 (s, 1H); 7.85 (s, 1H); 5.9 (s, NH₂).

5.2 5-Fluoro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid

0.5 g (2.10 mmol) of 2-amino-3-iodo-5-fluoropyridine obtained in Stage5.1, 0.55 g (6.3 mmol) of pyruvic acid, 0.71 g (6.3 mmol) of1,4-diazabicyclo[2.2.2]octane (DABCO) and 15 mL of anhydrousdimethylformamide are introduced into a 25-mL sealed tube, equipped witha magnetic stirrer and bubbled with argon. After some minutes, 0.05 g(0.22 mmol) of palladium acetate is added. The reaction mixture isstirred and bubbled with argon for 20 minutes, then it is quickly sealedand heated to 100° C. for 2.5 h. The cooled solution is concentrated atreduced pressure. The residue is then taken up in ethyl acetate (100 mL)and water (75 mL). The organic phase is washed with water then extractedwith 2×50 mL of aqueous solution of 2N sodium hydroxide. The basicaqueous phases are combined, cooled to 0° C. then acidified by addinghydrochloric acid (pH 3). The mixture is extracted with ethyl acetate(4×50 mL), the combined organic phases are dried over sodium sulfate andthen concentrated at reduced pressure. We obtain 0.158 g (0.88 mmol) ofthe expected product in the form of a yellow powder.

¹H NMR (DMSO D₆), δ (ppm): 13.2 (s, 1H); 12.4 (s, 1H); 8.4 (d, 1H); 7.95(dd, 1H); 7.1 (d, 1H).

5.3 5-Fluoro-1H-pyrrolo[2,3-b]pyridine-2-ethyl carboxylate

0.2 g (1.11 mmol) of acid obtained in Stage 5.2 and 10 mL of ethanol areput in a 100-mL flask equipped with a magnetic stirrer. 1 mL ofconcentrated sulfuric acid is added to the reaction mixture, which isthen refluxed for 18 hours. The cooled solution is concentrated todryness at reduced pressure. The residue is taken up in ethyl acetate(50 mL) and washed successively with normal aqueous solution of sodiumhydroxide (2×10 mL), with water (10 mL) and then with a saturatedaqueous solution of sodium chloride. The organic phase is dried oversodium sulfate and then concentrated at reduced pressure. 0.21 g of theexpected product is isolated.

¹H NMR (DMSO D₆), δ (ppm): 12.6 (s, NH); 8.4 (d, 1H); 8.0 (dd, 1H); 7.1(d, 1H); 4.35 (q, 2H); 1.35 (t, 3H).

5.45-Fluoro-1-[(3-fluorophenyl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-ethylcarboxylate

0.18 g (1.44 mmol) of 3-fluorobenzyl alcohol then 0.39 g (1.44 mmol) oftriphenylphosphine are added successively, while stirring, to a solutionof 0.2 g (0.96 mmol) of product obtained in Stage 5.3, in 15 mL of drytetrahydrofuran, under an inert atmosphere. Then 0.26 g (1.44 mmol) ofdiethyl azodicarboxylate is added dropwise at 0° C. The reaction mixtureis stirred for 20 h at room temperature and is then concentrated atreduced pressure. The resultant oil is purified by chromatography on acolumn of silica gel, eluting with a mixture of dichloromethane andmethanol. 0.26 g (0.82 mmol) of the expected product is isolated.

5.55-Fluoro-1-[(3-fluorophenyl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxylicacid

A mixture of 1.3 g (4.11 mmol) of5-fluoro-1-[(3-fluorophenyl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-ethylcarboxylate, obtained in Stage 5.4, in 40 mL of ethanol and of 0.7 g(12.33 mmol) of potassium hydroxide in 2 mL of water is heated for twohours under reflux. After this time, the mixture is concentrated todryness and taken up in 100 mL of water. The pH of the resultantsolution is acidified with additions of concentrated hydrochloric acidsolution. The precipitate is collected by filtration, rinsed with waterand then it is dried at reduced pressure. In this way we isolate 1.2 gof a beige solid, which will be used in the rest of the synthesiswithout further purification.

m.p.=197-198° C.

5.6N-[6-(Pyrrolidin-1-yl)pyridin-3-yl]-5-fluoro-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide(compound No. 5 in Table 2)

A solution of 0.4 g (1.39 mmol) of the acid obtained in Stage 5.5 and of0.25 g (1.53 mmol) of 1,1′-carbonyldiimidazole in 22 mL of drytetrahydrofuran is stirred for 3 h at 50° C. After this time, a solutionof 0.426 g (1.8 mmol) of 3-amino-6-(pyrrolidin-1-yl)pyridinehydrochloride (WO200248152) and 0.3 mL (2.16 mmol) of triethylamine in 6mL of tetrahydrofuran is added. The reaction mixture is stirred for 15hours at 30° C. then poured into 100 mL of water. The resultant mixtureis extracted with 3×50 mL of ethyl acetate. The organic phases arecombined, washed with 50 mL of water, dried over sodium sulfate and thenconcentrated at reduced pressure. The solid obtained is triturated in1.5 mL of methanol, then collected by filtration and dried. We thusobtain 0.18 g of a white solid.

m.p.=239-240° C.

N-[6-(Pyrrolidin-1-yl)pyridin-3-yl]-5-fluoro-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamidehydrochloride (2:3)

The compound obtained is taken up in 3.5 mL of a solution of 0.1Nhydrochloric acid in isopropanol. The resultant solid is filtered, thendried at reduced pressure. In this way we isolate 0.12 g of the expectedproduct in the form of hydrochloride.

m.p.=241-242° C.; Hydrochloride (2:3)

¹H NMR (DMSO D₆), δ (ppm): 10.79 (s, 1H); 8.49 (m, 2H); 8.15 (m, 2H);7.52 (s, 1H); 7.29 (m, 1H); 7.12-6.8 (m, 4H); 5.9 (s, 2H); 3.51 (m, 4H);1.98 (m, 4H).

Example 6 Compound No. 6 in Table 2N-[6-(Pyrrolidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide6.1N-(6-Chloropyridin-3-yl)-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

According to a method similar to that described in Stage 1.4, byreacting 0.85 g (6.65 mmol) of 6-chloro-3-aminopyridine with 1.5 g (4.43mmol) of the acid obtained in Stage 1.3, we obtain 1.23 g of theexpected product in the form of a white powder.

m.p.=212-213° C.

¹H NMR (DMSO D₆), δ (ppm): 10.9 (s, 1H); 8.75 (m, 3H); 8.19 (dxd, 1H);7.61 (s, 1H); 7.5 (d, 1H); 7.29 (m, 1H); 7.1-6.8 (m, 3H); 5.96 (s, 2H).

6.2N-[6-(Pyrrolidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide(compound No. 6 in Table 2).

A solution of 0.1 g (0.22 mmol) of the product obtained in Stage 6.1,0.19 mL (0.158 mmol) of pyrrolidine and 0.5 mL of N-methylpyrrolidinone,placed in a sealed tube, is heated in a microwave oven for 20 min at200° C. and 300 W. 100 mL of water is added to the reaction mixture andit is then extracted three times with 50 mL of ethyl acetate. Theorganic phases are combined, washed three times with 20 mL of water,dried over sodium sulfate and then concentrated at reduced pressure. Theproduct obtained is then purified by chromatography on a silica column,eluting with a mixture of dichloromethane and methanol, thenrecrystallized from a mixture of ethyl acetate and heptane. We obtain 60mg of the expected product in the form of white crystals.

m.p.: 234-236° C.

¹H NMR (DMSO D₆), δ (ppm): 10.32 (s, 1H); 8.75 (m, 1H); 8.66 (m, 1H);8.29 (d, 1H); 7.74 (dxd, 1H); 7.5 (s, 1H); 7.29 (m, 1H); 7.1-6.8 (m,3H); 6.4 (d, 1H); 5.91 (s, 2H); 3.32 (m, 4H); 1.91 (m, 4H).

Example 7 Compound No. 7 in Table 2N-[5-(Pyrrolidin-1-yl)pyrazin-2-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide7.1 2-Amino-5-(pyrrolidin-1-yl)pyrazine (Amine Vb)

A solution of 0.6 g (3.45 mmol) of 2-amino-5-bromopyrazine and of 3 mL(36 mmol) of pyrrolidine, placed in a sealed tube, is heated in amicrowave oven for two hours at 180° C. and 200 W. 100 mL of water isadded to the reaction mixture and it is extracted three times with 50 mLof ethyl acetate. The organic phases are combined, washed three timeswith 20 mL of water and then once with 20 mL of a saturated aqueoussolution of sodium chloride, dried over sodium sulfate and thenconcentrated at reduced pressure. The product obtained is then purifiedby chromatography on a silica column, eluting with a mixture ofdichloromethane and methanol. We obtain 0.21 g of the expected compoundin the form of a brown solid.

¹H NMR (DMSO D₆), δ (ppm): 7.5 (d, 1H); 7.32 (d, 1H); 5.15 (s, 2H); 3.25(m, 4H); 1.88 (m, 4H).

7.2N-[5-(Pyrrolidin-1-yl)pyrazin-2-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide(compound No. 7 in Table 2)

Compound No. 7 was prepared by a method similar to that described inStage 1.4 by reacting 0.126 g (0.77 mmol) of the amine obtained in Stage7.1 with 0.2 g (0.59 mmol) of the acid obtained in Stage 1.3. We obtain96 mg of the expected product in the form of a yellow solid.

m.p.=182-183° C.

¹H NMR (DMSO D₆), δ (ppm): 10.9 (s, 1H); 8.79 (m, 1H); 8.67 (m, 1H); 8.1(m, 1H); 7.79 (s, 1H); 7.65 (s, 1H); 7.3 (m, 1H); 7.1-6.85 (m, 3H); 5.98(s, 2H); 3.41 (m, 4H); 1.95 (m, 4H).

Example 8 Compound No. 8 in Table 2N-[6-(N,N-Dimethylamino)pyridazin-3-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

Compound No. 8 was prepared by a method similar to that described inStage 1.4 by reacting 0.098 g (0.71 mmol) of3-amino-6-(N,N-dimethylamino)pyridazine (US1977805419) with 0.2 g (0.59mmol) of the acid obtained in Stage 1.3. We thus obtain 73 mg of theexpected product in the form of a solid.

m.p.=224-226° C.

¹H NMR (DMSO D₆), δ (ppm): 11.3 (s, 1H); 8.8 (m, 1H); 8.71 (m, 1H); 7.89(d, 1H); 7.72 (s, 1H); 7.35-6.8 (m, 5H); 5.94 (s, 2H); 3.05 (s, 6H).

Example 9 Compound No. 9 in Table 2N-[6-(Pyrrolidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-[(4-pyridyl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxamide9.15-Trifluoromethyl-1-[(4-pyridyl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-ethylcarboxylate

Add successively, while stirring, 0.63 g (5.81 mmol) of(pyridin-4-yl)methanol then 1.52 g (5.81 mmol) of triphenylphosphine toa solution of 1 g (3.87 mmol) of the product obtained in Stage 1.1, in20 mL of dry tetrahydrofuran, under an inert atmosphere. Then add,dropwise, 1.01 g (5.81 mmol) of diethyl azodicarboxylate. The reactionmixture is then stirred for 20 h at room temperature and is thenconcentrated at reduced pressure. The resultant oil is purified bychromatography on a column of silica gel, eluting with a mixture ofheptane and ethyl acetate. 1.23 g of the expected product is isolated inthe form of a white solid.

¹H NMR (DMSO D₆), δ (ppm): 8.8 (d, 1H); 8.7 (d, 1H); 8.45 (d, 2H); 7.55(s, 1H); 6.95 (d, 2H); 5.9 (s, 2H); 4.3 (q, 2H); 1.2 (t, 3H).

9.25-Trifluoromethyl-1-[(4-pyridyl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxylicacid

A solution of 0.39 g (6.87 mmol) of potassium hydroxide in 2 mL of wateris added to a solution, in 30 mL of ethanol, of 0.8 g (2.29 mmol) of5-trifluoromethyl-1-[(4-pyridyl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-ethylcarboxylate, obtained in Stage 9.1. The mixture is stirred for fourhours under reflux. After this time the reaction mixture is concentratedat reduced pressure, and is then taken up in 40 mL of water. Thereaction mixture is acidified to pH 5 by successive additions ofconcentrated hydrochloric acid. The precipitate is collected byfiltration, washed with water and then dried at reduced pressure. Inthis way we isolate 0.54 g of the expected product, in the form of awhite powder, which is used as it is in the next stage.

m.p.=302-303° C.

9.3N-[6-(Pyrrolidin-1-yl)pyridin-3-yl]-]-5-trifluoromethyl-1-[(4-pyridyl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxamide(compound No. 9 in Table 2)

Compound No. 9 was prepared by a method similar to that described inStage 5.6 by reacting 0.3 g (0.93 mmol) of the acid obtained in Stage9.2 with 0.286 g (1.21 mmol) of 3-amino-6-(pyrrolidin-1-yl)pyridinehydrochloride (WO200248152), dissolved beforehand in a mixture of 0.2 mLof triethylamine and 5 mL of tetrahydrofuran. In this way we isolate 30mg of the expected product in the form of a yellow solid.

m.p.=244-245° C.

¹H NMR (DMSO D₆), δ (ppm): 10.39 (s, 1H); 8.71 (dxd, 2H); 8.41 (dxd,2H); 8.28 (d, 1H); 7.73 (dxd, 1H); 7.59 (s, 1H); 7 (d, 2H); 6, 41 (d,1H); 5.97 (s, 2H); 3.31 (m, 4H); 1.9 (m, 4H).

Example 10 Compound No. 16 in Table 3N-[6-(Pyrrolidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide10.1 3-Amino-2-iodo-6-(trifluoromethyl)pyridine

1.56 g (6.17 mmol) of iodine is added, in several portions, to amixture, stirred under argon at 20° C., of 1 g (6.17 mmol) of3-amino-6-trifluoromethylpyridine and 1.25 g (6.17 mmol) of silversulfate in 40 mL of ethanol. Stirring is maintained for 18 hours. Theinsoluble matter is removed by filtration and is washed with ethanol,the filtrate is concentrated at reduced pressure, and the residue istaken up in 100 mL of dichloromethane. The organic phase is washedsuccessively with 20 mL of 5% aqueous solution of sodium hydroxide, 40mL of water and 20 mL of saturated aqueous solution of sodium chloride,dried over sodium sulfate, concentrated at reduced pressure, and thenpurified by chromatography on a silica column (eluents: heptane-ethylacetate). In this way we isolate 1.17 g of the expected product, whichis used as it is in the rest of the synthesis.

10.2 (5-Trifluoromethyl)pyrrolo[3,2-b]pyridine-2-carboxylic acid

0.5 g (1.74 mmol) of 3-amino-2-iodo-6-(trifluoromethyl)pyridine,obtained in Stage 10.1, 0.45 g (5.21 mmol) of pyruvic acid, 0.51 mL(5.21 mmol) of 1,4-diazabicyclo[2.2.2]octane and 10 mL of drydimethylformamide are introduced, under argon, into a sealed tube. Thesolution is degassed for some minutes, then 0.19 g (0.87 mmol) ofpalladium acetate is added, the tube is closed and it is refluxed at130° C. for 4 hours. The cooled solution is then concentrated at reducedpressure and the residue is taken up in 100 mL of ethyl acetate. Theorganic phase is extracted successively with 2×50 mL of an aqueoussolution of 2N sodium hydroxide. The basic aqueous phases are combined,cooled to 0° C., acidified with additions of hydrochloric acid and thenextracted with 4×50 mL of ethyl acetate. These organic phases arecombined, washed with 20 mL of a saturated aqueous solution of sodiumchloride, dried over sodium sulfate and then concentrated at reducedpressure. We obtain 0.22 g of product, which is used as it is in thenext stage.

10.3 5-(Trifluoromethyl)pyrrolo[3,2-b]pyridine-2-ethyl carboxylate

1 mL (18.71 mmol) of concentrated sulfuric acid is added to a solutionof 0.2 g (0.87 mmol) of5-trifluoromethyl-pyrrolo[3,2-b]pyridine-2-carboxylic acid, obtained inStage 10.2, in 10 mL of ethanol. It is stirred under reflux for 20 hoursthen the solution is cooled, and concentrated at reduced pressure. Theresultant residue is then taken up in 50 mL of dichloromethane thenwashed successively with 20 mL of a saturated aqueous solution of sodiumbicarbonate, 40 mL of water and 20 mL of saturated aqueous solution ofsodium chloride, dried over sodium sulfate and then concentrated atreduced pressure. We obtain 0.19 g of product, which is used as it is inthe next stage.

10.41-(3-Fluorobenzyl)-5-(trifluoromethyl)pyrrolo[3,2-b]pyridine-2-ethylcarboxylate

Add, successively, 0.13 mL (1.16 mmol) of 3-fluorobenzyl alcohol, 0.3 g(1.16 mmol) of triphenylphosphine then 0.2 g (1.16 mmol) of diethylazodicarboxylate to a solution of 0.2 g (0.77 mL) of5-(trifluoromethyl)pyrrolo[3,2-b]pyridine-2-ethyl carboxylate, obtainedin Stage 10.3, in 120 mL of dry tetrahydrofuran, held at 0° C. underargon. The reaction mixture is stirred for 20 hours at 20° C. and isthen concentrated at reduced pressure. The resultant residue is purifiedby chromatography on a silica column (eluents: heptane-ethyl acetate).In this way we isolate 0.21 g of the expected product in the form of ayellow oil.

10.51-(3-Fluorobenzyl)-5-trifluoromethyl-pyrrolo[3,2-b]pyridine-2-carboxylicacid

The compound was prepared by a method similar to that described in Stage9.2 by reacting 0.6 g (1.64 mmol) of the ester obtained in Stage 10.4with 0.275 g (4.91 mmol) of potassium hydroxide. We obtain 0.47 g of theexpected product in the form of a white solid.

m.p.=254-255° C.

LCMS: [MH]⁺=339; purity 98%

10.6N-[6-(Pyrrolidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxamide(compound No. 16 in Table 3)

Compound No. 10 was prepared by a method similar to that described inStage 1.4 by reacting 0.25 g (0.74 mmol) of the acid obtained in Stage10.5 with 0.2 g (0.89 mmol) of 3-amino-6-(pyrrolidin-1-yl)pyridinehydrochloride (WO200248152), dissolved beforehand in a mixture of 0.13mL of triethylamine and 3 mL of dimethylformamide. In this way weisolate 40 mg of the expected product in the form of a yellow solid.

m.p.=219-220° C.

¹H NMR (DMSO D₆), δ (ppm): 10.4 (s, 1H); 8.3 (m, 2H); 7.74 (m, 2H); 7.56(s, 1H); 7.3 (m, 1H); 7.1-6.82 (m, 3H); 6, 41 (d, 1H); 5.91 (s, 2H);3.37 (m, 4H); 1.91 (m, 4H).

Example 11 Compound No. 10 in Table 2N-[6-(Isopropylamino)pyridin-3-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

According to a method similar to that described in Stage 6.2, byreacting 0.15 g (0.33 mmol) ofN-(6-chloropyridin-3-yl)-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide,obtained in Stage 6.1, with 0.29 mL (3.34 mmol) of isopropylamine, weobtain 50 mg of the expected product in the form of a light yellowpowder.

m.p.=210-212° C.

¹H NMR (DMSO D₆), δ (ppm): 10.32 (s, 1H); 8.79 (d, 1H); 8.71 (d, 1H);8.2 (m, 1H); 7.61 (dxd, 1H); 7.51 (s, 1H); 7.31 (m, 1H); 7.12-6.86 (m,3H); 6.42 (d, 1H); 6.25 (d, 1H); 5.95 (s, 2H); 3.91 (sext., 1H); 1.12(d, 6H).

Example 12 Compound No. 15 in Table 2N-[6-(Azetidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamidehydrochloride (1:1) 12.1 2-(Azetidin-1-yl)-5-nitropyridine

Add, dropwise, 4.7 g (80.76 mmol) of azetidine to a suspension, stirredat 20° C., of 27.9 g (0.201 mole) of potassium carbonate and 11 g (67.3mmol) of 2-chloro-5-nitropyridine in 100 mL of dimethylformamide. Stirthe mixture for 5 minutes at 20° C., then for 6 hours at 70° C. Afterthis time, the suspension is poured into a mixture of 300 mL of waterand 300 mL of ethyl acetate. The aqueous phase is separated, thenextracted with 200 mL of ethyl acetate. The organic phases are combined,washed three times with 250 mL of water, then dried over sodium sulfateand concentrated at reduced pressure. We thus obtain 11.7 g of theexpected product in the form of a solid.

m.p.=132-134° C.

¹H NMR (CDCl₃), δ (ppm): 8.92 (d, 1H); 8.09 (dxd, 1H); 6.07 (d, 1H);4.12 (m, 4H); 2.46 (quint., 2H).

12.2 3-Amino-6-(azetidin-1-yl)-pyridine (Amine Vc)

A suspension of 11.5 g (64.18 mmol) of2-(azetidin-1-yl)-5-nitropyridine, prepared in the preceding stage, and1 g of Pd/C at 10% in 400 mL of ethanol is stirred vigorously at 20° C.under 5 atm of hydrogen for 4 hours. After this time, the mixture isfiltered on a Celite pad and then concentrated at reduced pressure. Wethus obtain 9.3 g of the expected product, which is used as it is in therest of the synthesis.

¹H NMR (DMSO D₆), δ (ppm): 7.57 (d, 1H); 6.92 (dxd, 1H); 6.2 (d, 1H);4.46 (broadened peak, 2H); 3.78 (m, 4H); 2.25 (quint., 2H).

12.3N-[6-(Azetidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide(Compound No. 15 in Table 2)

Add, dropwise, 4.26 g (24.83 mmol) of diethyl cyanophosphonate to asolution, stirred at 20° C. under a nitrogen atmosphere, of 7 g (20.69mmol) of5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxylicacid as obtained in Stage 1.3 and 3.7 g (24.83 mmol) of3-amino-6-(azetidin-1-yl)-pyridine prepared in the preceding stage in140 mL of dimethylformamide. Then add, dropwise, 4.6 mL (45.53 mmol) oftriethylamine, then stir the reaction mixture for 70 hours at 20° C.After this time, the mixture is concentrated at reduced pressure andthen taken up in 700 mL of ethyl acetate and 300 mL of water. Theaqueous phase is separated and then extracted with 200 mL of ethylacetate. The organic phases are combined, washed three times with 200 mLof a saturated sodium bicarbonate solution, then dried over sodiumsulfate and concentrated at reduced pressure. The product thus obtainedis purified in a silica column, eluting with a mixture ofdichloromethane and ethyl acetate, then recrystallized from a mixture ofethanol and methanol. In this way we isolate 5.7 g of the expectedproduct in the form of white crystals.

m.p.=243-244° C.

12.4N-[6-(Azetidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamidehydrochloride (1:1) (Compound No. 15 in Table 2)

2.6 mL of a 2M solution of hydrochloric acid is added to a solution of1.2 g ofN-[6-(azetidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide,prepared in the preceding stage, in 50 mL of dichloromethane. Thesolution is concentrated to dryness and the resultant solid isrecrystallized from ethanol. In this way we isolate 0.62 g of theexpected salt.

m.p.=230-235° C.

¹H NMR (DMSO D₆), δ (ppm): 10.98 (s, 1H); 8.87 (s, 1H); 8.79 (s, 1H);8.47 (s, 1H); 8.2 (dxd, 1H); 7.71 (s, 1H); 7.31 (m, 1H); 7.08 (m, 1H);6.89 (m, 3H); 5.98 (s, 2H); 4.25 (m, 4H); 2.42 (quint., 2H).

Example 13 Compound No. 19 in Table 2N-[6-(3,3-Difluoroazetidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide13.1 2-(3,3′-Difluoroazetidin-1-yl)-5-nitropyridine

A mixture of 0.367 g (2.84 mmol) of 3,3-difluoroazetidine hydrochloride,0.3 g (1.89 mmol) of 2-chloro-5-nitropyridine and 0.41 mL (2.84 mmol) oftriethylamine in 10 mL of dimethylformamide is heated overnight at 100°C. After this time, the suspension is poured into a mixture of 30 mL ofwater and 30 mL of ethyl acetate. The aqueous phase is separated, andthen extracted with 20 mL of ethyl acetate. The organic phases arecombined, washed three times with 25 mL of water, then dried over sodiumsulfate and concentrated at reduced pressure. The resultant product ispurified by chromatography on a silica column, eluting withdichloromethane. We thus obtain 0.34 g of the expected product in theform of a yellow solid.

¹H NMR (DMSO D₆), δ (ppm): 9 (d, 1H); 8.32 (dxd, 1H); 6.61 (d, 1H); 4.6(m, 4H).

13.2 3-Amino-6-(3,3-difluoroazetidin-1-yl)pyridine (Amine Vh)

A suspension of 0.34 g (1.58 mmol) of2-(3,3-difluoroazetidin-1-yl)-5-nitropyridine, prepared in the precedingstage, and 8 mg of Pd/C at 10% in 10 mL of ethanol is stirred vigorouslyat 20° C. under 5 atm of hydrogen for 4 hours. After this time, themixture is filtered on a Celite pad, then concentrated at reducedpressure. The resultant product is purified by chromatography on asilica column, eluting with a mixture of dichloromethane and methanol.We thus obtain 0.188 g of the expected product in the form of a redpowder, which is used as it is in the rest of the synthesis.

¹H NMR (DMSO D₆), δ (ppm): 7.6 (s, 1H); 6.96 (dxd, 1H); 6.4 (d, 1H);4.67 (s, 2H); 4.2 (t, 4H).

13.3N-[6-(3,3-Difluoroazetidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide(compound No. 19 in Table 2)

Compound No. 19 was prepared by a method similar to that described inStage 1.4 by reacting 0.188 g (0.02 mmol) of3-amino-6-(3,3-difluoroazetidin-1-yl)pyridine, prepared in the precedingstage, with 0.23 g (0.68 mmol) of the acid obtained in Stage 1.3. Wethus obtain 140 mg of the expected product in the form of a solid.

m.p.=222-224° C.

¹H NMR (DMSO D₆), δ (ppm): 10.6 (s, 1H); 8.84 (s, 1H); 8.74 (s, 1H);8.44 (s, 1H); 7.98 (d, 1H); 7.6 (s, 1H); 7.32 (m, 1H); 7.08 (txd, 1H);6.92 (m, 2H); 6.64 (d, 1H); 6 (s, 2H); 4.39 (m, 4H).

Example 14 Compound No. 20 in Table 2N-[6-(3-Hydroxyazetidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide14.1 2-(3-Hydroxyazetidin-1-yl)-5-nitropyridine

A mixture of 0.311 g (2.84 mmol) of 3-hydroxyazetidine hydrochloride,0.3 g (1.89 mmol) of 2-chloro-5-nitropyridine and 0.41 mL (2.84 mmol) oftriethylamine in 10 mL of dimethylformamide is heated overnight at 100°C. After this time, the suspension is poured into a mixture of 30 mL ofwater and 30 mL of ethyl acetate. The aqueous phase is separated, andthen extracted with 20 mL of ethyl acetate. The organic phases arecombined, washed three times with 25 mL of water, then dried over sodiumsulfate and concentrated at reduced pressure. We thus obtain 0.34 g ofthe expected product in the form of a solid, which will be used as it isin the rest of the synthesis.

¹H NMR (DMSO D₆), δ (ppm): 8.95 (s, 1H); 8.21 (dxd, 1H); 6.41 (d, 1H);5.85 (d, 1H); 4.62 (m, 1H); 4.37 (m, 2H); 3.9 (m, 2H).

14.2 3-Amino-6-(3-hydroxyazetidin-1-yl)pyridine (Amine Ve)

A suspension of 0.34 g (1.74 mmol) of2-(3-hydroxyazetidin-1-yl)-5-nitropyridine, prepared in the precedingstage, and 9 mg of Pd/C at 10% in 10 mL of ethanol is stirred vigorouslyat 20° C. under 5 atm of hydrogen for 4 hours. After this time, themixture is filtered on a Celite pad and then concentrated at reducedpressure. The resultant product is purified by chromatography on asilica column, eluting with a mixture of dichloromethane and methanol.We thus obtain 0.1 g of the expected product, which will be used as itis in the rest of the synthesis.

¹H NMR (DMSO D₆), δ (ppm): 7.58 (s, 1H); 6.91 (d, 1H); 6.22 (d, 1H);5.48 (broadened peak, 1H); 4.48 (broadened peak, 3H); 3.98 (m, 2H); 3.49(m, 2H).

14.3N-[6-(3-Hydroxyazetidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide(compound No. 20 in Table 2)

Compound No. 20 was prepared by a method similar to that described inStage 1.4 by reacting 99 mg (0.6 mmol) of3-amino-6-(3-hydroxyazetidin-1-yl)-pyridine, prepared in the precedingstage, with 0.135 g (0.4 mmol) of the acid obtained in Stage 1.3. Wethus obtain 103 mg of the expected product in the form of a solid.

m.p.=221-223° C.

¹H NMR (DMSO D₆), δ (ppm): 10.51 (s, 1H); 8.87 (s, 1H); 8.78 (s, 1H);8.36 (s, 1H); 7.87 (d, 1H); 7.59 (s, 1H); 7.35 (m, 1H); 7.09 (m, 1H);6.95 (m, 2H); 6.45 (d, 1H); 6 (s, 2H); 5.61 (s, 1H); 4.59 (m, 1H); 4.15(m, 2H); 3.68 (m, 2H).

Example 15 Compound No. 22 in Table 2N-[4-Methyl-6-(pyrrolidin-1-yl)pyridin-3-yl]-6-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide15.16-Trifluoromethyl-1-[(3-fluorophenyl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-methylcarboxylate

According to a method similar to that described in Stage 1.2, byreacting 1.5 g (6.14 mmol) of6-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine-2-methyl carboxylate and 1mL (9.21 mmol) of 3-fluorobenzyl alcohol, we obtain 2.1 g of theexpected compound.

¹H NMR (CDCl₃), δ (ppm): 8.3 (d, 1H); 7.69 (d, 1H); 7.48 (s, 1H);7.4-7.19 (m, 2H); 7.08 (m, 2H); 6.11 (s, 2H); 4.05 (s, 3H).

15.26-Trifluoromethyl-1-[(3-fluorophenyl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxylicacid

According to a method similar to that described in Stage 1.3, startingfrom 2.1 g (5.96 mmol) of6-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-methylcarboxylate, prepared in the preceding stage, we obtain 2 g of theexpected compound.

¹H NMR (DMSO D₆), δ (ppm): 8.39 (d, 1H); 7.64 (d, 1H); 7.32 (m, 1H);7.24 (s, 1H); 7.05 (m, 3H); 6.02 (s, 2H).

15.3N-[4-Methyl-6-(pyrrolidin-1-yl)pyridin-3-yl]-6-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide(compound No. 22 in Table 2)

Compound No. 22 was prepared by a method similar to that described inStage 1.4 by reacting 0.314 g (1.77 mmol) of3-amino-4-methyl-6-(pyrrolidin-1-yl)pyridine (WO05/035526) with 0.5 g(0.1.48 mmol) of the acid obtained in the preceding stage. We thusobtain 0.24 g of the expected product in the form of a solid.

m.p.=202-203° C.

¹H NMR (DMSO D₆), δ (ppm): 10.09 (s, 1H); 8.5 (d, 1H); 7.87 (s, 1H);7.72 (d, 1H); 7.5 (s, 1H); 7.32 (m, 1H); 7.08 (m, 1H); 6.95 (m, 2H);6.38 (s, 1H); 5.94 (s, 2H); 3.39 (m, 4H); 2.06 (s, 3H); 1.95 (m, 4H).

Example 16 Compound No. 33 in Table 2N-[6-(Pyrrolidin-1-yl)pyridin-3-yl]-6-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide16.1N[6-Chloropyridin-3-yl]-6-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

According to a method similar to that described in Stage 6.1, byreacting 0.5 g (1.48 mmol) of6-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxylicacid, described in Stage 15.2 with 0.288 (2.22 mmol) of3-amino-6-chloropyridine, we obtain 0.33 g of the expected compound inthe form of a white solid.

m.p.=202-203° C.

¹H NMR (DMSO D₆), δ (ppm): 10.95 (s, 1H); 8.75 (d, 1H); 8.58 (d, 1H);8.22 (d, 1H); 7.76 (d, 1H); 7.61 (s, 1H); 7.53 (d, 1H); 7.32 (m, 1H);7.05 (m, 1H); 6.98 (m, 2H); 5.94 (s, 2H).

16.2N-[6-(Pyrrolidin-1-yl)pyridin-3-yl]-6-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide(Product No. 33 in Table 2)

According to a method similar to that described in Stage 6.2, byreacting 0.3 g (0.67 mmol) ofN[6-chloropyridin-3-yl]-6-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide,described in the preceding stage, with 0.56 mL (6.68 mmol) ofpyrrolidine, we obtain 0.21 g of the expected compound.

m.p.=204-205° C.

¹H NMR (DMSO D₆), δ (ppm): 10.5 (s, 1H); 8.58 (d, 1H); 8.39 (d, 1H);7.87 (dxd, 1H); 7.79 (d, 1H); 7.59 (s, 1H); 7.4 (m, 1H); 7.12 (m, 1H);7.07 (m, 2H); 6.53 (d, 1H); 6.01 (s, 2H); 3.46 (m, 4H); 2 (m, 4H).

Example 17 Compound No. 34 in Table 2N-[6-(Pyrrolidin-1-yl)-4-trifluoromethylpyridin-3-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide17.1 6-(Pyrrolidin-1-yl)-4-(trifluoromethyl)pyridine-3-methylcarboxylate

A mixture of 2.5 g (10.43 mmol) of 6-chloro-4-trifluoromethyl-methylnicotinate, 2.88 g (20.87 mmol) of potassium carbonate and 2.61 mL (31.3mmol) of pyrrolidine in 90 mL of dimethylformamide is heated at 100° C.for 3 hours. The reaction mixture is then concentrated at reducedpressure and is then taken up in 100 mL of water. The precipitate iscollected by filtration and is washed with 150 mL of water. After dryingat reduced pressure, 2.5 g of the expected compound is isolated.

¹H NMR (CDCl₃), δ (ppm): 2.11 (m, 4H); 3.61 (broadened peak, 4H); 3.93(s, 3H); 6.69 (s, 1H); 8.89 (s, 1H).

17.2 6-(Pyrrolidin-1-yl)-4-(trifluoromethyl)pyridine-3-carboxylic acid

A mixture of 2.5 g (9.12 mmol) of6-(pyrrolidin-1-yl)-4-(trifluoromethyl)pyridine-3-methyl carboxylate,obtained in the preceding stage, and 0.76 g (13.67 mmol) of potassiumhydroxide in 50 mL of methanol and 2 mL of water is heated at 20° C. for24 hours. The mixture is then concentrated at reduced pressure. Then 100mL of water is added and the solution is washed with 100 mL ofdichloromethane, then acidified to pH 4 with additions of concentratedhydrochloric acid. A precipitate is collected by filtration and is thenwashed with 50 mL of water. After drying at reduced pressure, 2.2 g ofthe expected compound is isolated.

¹H NMR (DMSO D₆), δ (ppm): 1.99 (s, 4H); 3.51 (broadened peak, 4H); 6.71(s, 1H); 8.72 (s, 1H).

17.36-(Pyrrolidin-1-yl)-4-trifluoromethyl-3-(terbutoxycarbonylamino)pyridine

A mixture of 2.2 g (8.45 mmol) of6-(pyrrolidin-1-yl)-4-(trifluoromethyl)pyridine-3-carboxylic acid,obtained in the preceding stage, 2.37 mL (10.99 mmol) ofdiphenylphosphorylazide and 2.95 mL (21.14 mmol) of triethylamine in 25mL of tert-butanol is heated at 90° C. for 5 hours. The reaction mixtureis then concentrated at reduced pressure, taken up in 50 mL of water,then extracted 3 times with 50 mL of dichloromethane. The organic phasesare combined, washed with 50 ml of water, dried over sodium sulfate andthen concentrated at reduced pressure. The oil obtained is purified bychromatography on a silica column, eluting with a mixture ofdichloromethane and methanol. In this way we isolate 1.05 g of theexpected product.

¹H NMR (CDCl₃), δ (ppm): 1.53 (s, 9H); 2.09 (m, 4H); 3.51 (m, 4H); 6.2(broadened peak, 1H); 6.52 (s, 1H); 8.39 (broadened peak, 1H).

17.4 6-(Pyrrolidin-1-yl)-4-trifluoromethyl-3-aminopyridine hydrochloride(Amine Vg)

A solution of 1 g (3.02 mmol) of6-(pyrrolidin-1-yl)-4-trifluoromethyl-3-(terbutoxycarbonylamino)pyridine,prepared in the preceding stage, in 11 mL of 4N hydrochloric acid indioxane, is stirred for 5 hours under reflux. Then 200 mL of ethyl etheris added to the cooled reaction mixture. 0.8 g of a precipitate iscollected by filtration.

Melting point: 207-209° C.;

¹H NMR (DMSO D₆), δ (ppm): 2 (m, 4H); 3.52 (m, 4H); 7.1 (s, 1H); 7.49(broadened peak, 2H); 7.92 (s, 1H).

17.5N-[6-(Pyrrolidin-1-yl)-4-trifluoromethylpyridin-3-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide(compound No. 34 in the table)

Compound No. 34 was prepared by a method similar to that described inStage 1.4 by reacting 0.411 g (1.54 mmol) of6-(pyrrolidin-1-yl)-4-trifluoromethyl-3-aminopyridine hydrochloride,obtained in the preceding stage, with 0.4 g (0.18 mmol) of5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxylicacid obtained in Stage 1.3, the whole in the presence of 0.25 mL (1.77mmol) of triethylamine, 0.175 g (1.3 mmol) of 1-hydroxybenzotriazolemonohydrate and 0.25 g (1.3 mmol) ofN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride. We thusobtain 0.15 g of the expected product in the form of a solid.

m.p.=207-208° C.

¹H NMR (DMSO D₆), δ (ppm): 10.29 (s, 1H); 8.81 (s, 1H); 8.72 (s, 1H);8.09 (s, 1H); 7.57 (s, 1H); 7.32 (m, 1H); 7.09 (m, 1H); 6.99 (d, 1H);6.91 (d, 1H); 6.7 (s, 1H); 5.95 (s, 2H); 3.5 (m, 4H); 1.99 (m, 4H).

Example 18 Compound No. 35 in Table 2N-[5-Fluoro-6-(N,N-dimethylamino)pyridin-3-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

Compound No. 35 was prepared by a method similar to that described inStage 1.4 by reacting 0.4 g (1.18 mmol) of5-fluoro-6-(N,N-dimethylamino)-3-aminopyridine (WO2004/110986), with 0.4g (0.18 mmol) of5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxylicacid obtained in Stage 1.3. We thus obtain 0.33 g of the expectedproduct in the form of a solid.

m.p.=199-200° C.

¹H NMR (DMSO D₆), δ (ppm): 10.7 (s, 1H); 8.85 (s, 1H); 8.77 (s, 1H);8.29 (s, 1H); 7.89 (d, 1H); 7.6 (s, 1H); 7.32 (m, 1H); 7.09 (m, 1H);6.98 (m, 2H); 6 (s, 2H); 3.02 (s, 6H).

Example 19 Compound No. 36 in Table 2N-[2-(N,N-Dimethylamino)pyrimidin-5-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide19.1 N-(2-Chloropyrim idin-5-yl)-5-trifluoromethyl-1-(34luorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

According to a method similar to that described in Stage 1.4, startingfrom 1.08 g (3.2 mmol) of5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxylicacid, described in Stage 1.3, and 0.46 g (3.52 mmol) of2-chloro-5-aminopyrimidine, we obtain 0.33 g of the expected product.

19.2 N-[2-(N,N-Dim ethylamino)pyrimidin-5-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide(compound No. 36 in Table 2)

In a sealed tube, a mixture of 0.2 g (0.44 mmol) ofN-(2-chloropyrimidin-5-yl)-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide,prepared in the preceding stage, and 1.3 mL (8.89 mmol) of an aqueoussolution of dimethylamine at 40%, the whole in solution in 15 mL ofethanol, is heated at 110° C. for 20 h. After this time, the reactionmixture is allowed to return to room temperature, then a whiteprecipitate is collected by filtration, washed with water and dried atreduced pressure to obtain 0.14 g of the expected product.

m.p.=236-238° C.

¹H NMR (DMSO D₆), δ (ppm): 10.51 (s, 1H); 8.82 (s, 1H); 8.75 (s, 1H);8.6 (s, 2H); 7.56 (s, 1H); 7.32 (m, 1H); 7.08 (m, 1H); 6.96 (m, 2H);5.98 (s, 2H); 3.11 (s, 6H).

Example 20 Compound No. 37 in Table 2

N-[6-(3-Azabicyclo[3.2.0]hept-3-yl)pyridin-3-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

20.1 2-(3-Azabicyclo[3.2.0]hept-3-yl)-5-nitropyridine

A mixture of 0.1 g (0.63 mmol) of 2-chloro-5-nitropyridine, 0.1 g (0.75mmol) of 3-aza-bicyclo[3.2.0]heptane (J. Med. Chem. 1967, 10(4), 621)and 0.26 mL (0.19 mmol) of triethylamine in 10 mL of dioxane, is heatedat 65° C. for 4 h. The reaction mixture is then poured into 50 mL of icewater. The mixture is stirred until the ice has melted completely, thena yellow precipitate is collected by filtration and is dried at reducedpressure. In this way we isolate 0.121 g of the expected product in theform of a yellow powder.

¹H NMR (DMSO D₆), δ (ppm): 9 (d, 1H); 8.23 (dxd, 1H); 6.7 (d, 1H); 3.81(broadened peak, 2H); 3.51 (m, 2H); 3.09 (m, 2H); 2.27 (m, 2H); 1.71 (m,2H).

20.2 6-(3-Azabicyclo[3.2.0]hept-3-yl)-3-aminopyridine (Amine Va)

According to a procedure similar to that described in Stage 14.2,starting from 0.12 g (0.55 mmol) of2-(3-azabicyclo[3.2.0]hept-3-yl)-5-nitropyridine, prepared in thepreceding stage, and 0.17 g of palladium on charcoal at 10%, we obtain0.096 g of the expected compound.

¹H NMR (DMSO D₆), δ (ppm): 7.62 (d, 1H); 6.95 (d, 1H); 6.49 (d, 1H);4.42 (broadened peak, 2H); 3.52 (d, 2H); 2.98 (m, 4H); 2.21 (m, 2H);1.72 (m, 2H).

20.3N-[6-(3-Azabicyclo[3.2.0]hept-3-yl)pyridin-3-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide(compound No. 37 in Table 2)

According to a method similar to that described in Stage 12.3, startingfrom 0.12 g (0.35 mmol) of5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxylicacid, described in Stage 1.3, and 0.075 g (0.38 mmol) of6-(3-azabicyclo[3.2.0]hept-3-yl)-3-aminopyridine, prepared in thepreceding stage, we obtain 0.12 g of the expected product.

m.p.=172-174° C.

¹H NMR (DMSO D₆), δ (ppm): 10.45 (s, 1H); 8.81 (s, 1H); 8.71 (s, 1H);8.36 (s, 1H); 7.81 (d, 1H); 7.52 (s, 1H); 7.31 (m, 1H); 7.08 (m, 1H);6.92 (m, 2H); 6.62 (d, 1H); 5.98 (s, 2H); 3.67 (d, 2H); 3.2 (m, 2H);3.02 (m, 2H); 2.23 (m, 2H); 1.72 (m, 2H).

Example 21 Compound No. 38 in Table 2N-[6-(3-Azabicyclo[3.1.0]hex-3-yl)pyridin-3-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide21.1 2-(3-Azabicyclo[3.1.0]hex-3-yl)-5-nitropyridine

A mixture of 0.5 g (3.15 mmol) of 2-chloro-5-nitropyridine, 0.452 g(3.78 mmol) of 3-aza-bicyclo[3.2.0]heptane (J. Med. Chem. 1967, 10(4),621) and 1.32 mL (6.94 mmol) of triethylamine in 10 mL of dioxane, isheated at 65° C. for 4 h. The reaction mixture is then poured into 50 mLof ice water. The mixture is stirred until the ice has meltedcompletely, then a yellow precipitate is collected by filtration and isdried at reduced pressure. In this way we isolate 0.63 g of the expectedproduct in the form of a yellow powder.

¹H NMR (DMSO D₆), δ (ppm): 8.91 (d, 1H); 8.15 (dxd, 1H); 6.53 (d, 1H);3.95-3.45 (m, 4H); 1.75 (m, 2H); 0.77 (m, 1H); 0.65 (m, 1H).

21.2 6-(3-Azabicyclo[3.1.0]hex-3-yl)-3-aminopyridine (amine Vf)

According to a procedure similar to that described in Stage 14.2,starting from 0.6 g (2.92 mmol) of2-(3-azabicyclo[3.2.0]hex-3-yl)-5-nitropyridine, prepared in thepreceding stage, and 0.9 g of palladium on charcoal at 10%, we obtain0.49 g of the expected compound.

¹H NMR (DMSO D₆), δ (ppm): 7.55 (s, 1H); 6.99 (d, 1H); 6.25 (d, 1H);4.32 (broadened peak, 2H); 3.51 (d, 2H); 3.11 (m, 2H); 1.6 (m, 2H); 0.66(m, 1H); 0.2 (m, 1H).

21.3N-[6-(3-Azabicyclo[3.1.0]hex-3-yl)pyridin-3-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide(compound No. 38 in Table 2)

According to a method similar to that described in Stage 12.3, startingfrom 0.5 g (1.48 mmol) of 5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxylicacid, described in Stage 1.3, and 0.3 g (1.71 mmol) of6-(3-azabicyclo[3.1.0]hex-3-yl)-3-aminopyridine, prepared in thepreceding stage, we obtain 0.233 g of the expected product.

m.p.=212-214° C.

¹H NMR (DMSO D₆), δ (ppm): 10.42 (s, 1H); 8.81 (s, 1H); 8.72 (s, 1H);8.31 (s, 1H); 7.79 (d, 1H); 7.52 (s, 1H); 7.31 (m, 1H); 7.08 (m, 1H);6.93 (m, 2H); 6.48 (d, 1H); 5.97 (s, 2H); 3.63 (d, 2H); 3.31 (m, 2H);1.69 (m, 2H); 0.74 (m, 1H); 0.2 (m, 1H).

Example 22 Compound No. 39 in Table 2N-[6-(3-Azabicyclo[3.1.0]hex-3-yl)-pyridin-3-yl]-5-fluoro-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide22.1 5-Fluoro-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylicacid

A mixture of 6.9 g (20.58 mmol) of5-fluoro-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-ethylcarboxylate (WO07/010,138) and 1.89 g (33.7 mmol) of potassium hydroxidein a mixture of 80 mL of ethanol and 10 mL of water is heated underreflux for 1.5 h. After this time, the reaction mixture is concentratedat reduced pressure, and is then taken up in 200 mL of water. Thesolution is acidified with additions of concentrated hydrochloric acid,and then extracted three times with 50 mL of dichloromethane. Theorganic phases are combined, dried over sodium sulfate and thenconcentrated at reduced pressure. The resultant product is triturated in5 mL of dichloromethane. A precipitate is collected by filtration and isdried at reduced pressure. In this way we isolate 5.35 g of the expectedproduct, which is used as it is in the rest of the synthesis.

22.2N-[6-(3-Azabicyclo[3.1.0]hex-3-yl)-pyridin-3-yl]-5-fluoro-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide(compound No. 39 in Table 2)

According to a method similar to that described in Stage 12.3, startingfrom 0.45 g (1.56 mmol) of5-fluoro-1-[(3-fluorophenyl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxylicacid, described in the preceding stage, and 0.3 g (1.71 mmol) of6-(3-azabicyclo[3.1.0]hex-3-yl)-3-aminopyridine, prepared in Stage 21.2,we obtain 0.47 g of the expected product.

m.p.=222-224° C.

¹H NMR (DMSO D₆), δ (ppm): 10.32 (s, 1H); 8.47 (s, 1H); 8.31 (s, 1H);8.13 (d, 1H); 7.78 (d, 1H); 7.39 (s, 1H); 7.19 (m, 1H); 7.02 (m, 1H);6.92 (m, 2H); 6.47 (d, 1H); 5.9 (s, 2H); 3.62 (d, 2H); 3.31 (m, 2H);1.69 (m, 2H); 0.75 (m, 1H); 0.2 (m, 1H).

Example 23 Compound No. 171 in Table 23-[[5-[[[1-(3-Fluorobenzyl)-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-2-yl]carbonyl]amino]pyridin-2-yl]amino]ethylpropionate 23.1 3-[(5-Aminopyridin-2-yl)amino]ethyl propionate

A suspension of 2.3 g (9.61 mmol) of 3-[(5-nitropyridin-2-yl)amino]ethylpropionate (JP07/051,121) and 0.5 g of Raney Nickel in 96 mL of aceticacid is stirred for 7 hours, at 20° C. under 5 atm of hydrogen. Afterthis time, the reaction mixture is filtered on a Celite pad and thenconcentrated at reduced pressure. The product obtained is used as it isin the rest of the synthesis.

23.43-[[5-[[[1-(3-Fluorobenzyl)-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-2-yl]carbonyl]amino]pyridin-2-yl]amino]ethylpropionate

According to a method similar to that described in Example 1.4, startingfrom 0.558 g (2.67 mmol) of 3-[(5-aminopyridin-2-yl)amino]ethylpropionate, obtained in the preceding stage, and 0.3 g (0.89 mmol) of5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxylicacid, obtained according to Stage 1.3, we obtain 0.26 g of the expectedproduct.

LCMS: [MH]⁺=530

¹H NMR (DMSO D₆), δ (ppm): 10.4 (s, 1H); 8.81 (s, 1H); 8.71 (s, 1H);8.25 (s, 1H); 7.68 (d, 1H); 7.53 (s, 1H); 7.31 (m, 1H); 7.05 (m, 1H);6.92 (m, 2H); 6.59 (m, 1H); 6.51 (d, 1H); 5.96 (s, 2H); 4.1 (q, 2H); 3.5(m, 2H); 2.56 (m, 2H); 1.2 (t, 3H).

Example 24 Compound No. 40 in Table 23-[[5-[[[1-(3-Fluorobenzyl)-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridin-2-yl]carbonyl]amino]pyridin-2-yl]amino]propionicacid

A solution, in 10 mL of ethanol, of 0.26 g (0.49 mmol) of compound No.171 prepared in Example 23 and 1 mL (1 mmol) of a molar solution ofsodium hydroxide, is stirred at 20° C. for 20 h. After this time, themixture is concentrated at reduced pressure, and is then taken up in 100mL of water and 100 mL of ethyl acetate. The pH of the aqueous phase isacidified by successive additions of 1N hydrochloric acid solution. Theorganic phase is then separated, washed once with 100 mL of water, oncewith 50 mL of saturated sodium chloride solution, then dried overmagnesium sulfate and concentrated at reduced pressure. In this way weisolate 0.21 g of the expected product.

m.p.=196-199° C.

¹H NMR (DMSO D₆), δ (ppm): 12.1 (broadened peak, 1H); 10.39 (s, 1H); 8.8(s, 1H); 8.71 (s, 1H); 8.25 (s, 1H); 7.69 (d, 1H); 7.52 (s, 1H); 7.31(m, 1H); 7.07 (m, 1H); 6.92 (m, 2H); 6.5 (m, 2H); 5.96 (s, 2H); 3.46 (m,2H); 2.49 (m, 2H partially covered by the DMSO peak).

Example 25 Compound No. 41 in Table 2N-[6-(3-Hydroxypropylamino)pyridin-3-yl]-5-trifluoromethyl-1-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

A mixture, in 7.5 mL of tetrahydrofuran, of 0.2 g (0.38 mmol) ofcompound No. 171, prepared in Stage 23, 0.14 g (3.78 mmol) of sodiumborohydride and 0.15 mL (3.78 mmol) of methanol, is stirred for 48 hunder reflux. After this time, the reaction mixture is poured into 200mL of ice water. 1 mL of acetic acid is added, then the mixture isextracted twice with 100 mL of ethyl acetate. The organic phases arecombined, then washed twice with 100 mL of water, once with 50 mL ofsaturated sodium chloride solution, then dried over magnesium sulfateand concentrated at reduced pressure. The residue obtained is purifiedby chromatography on a silica column, eluting with a mixture ofdichloromethane and methanol. We thus obtain 67 mg of the expectedcompound.

m.p.=207-210° C.

¹H NMR (DMSO D₆), δ (ppm): 10.22 (s, 1H); 8.68 (s, 1H); 8.59 (s, 1H);8.09 (s, 1H); 7.52 (d, 1H); 7.4 (s, 1H); 7.17 (m, 1H); 6.91 (m, 1H); 6.8(m, 2H); 6.35 (d, 1H); 6.3 (m, 1H); 5.83 (s, 2H); 4.33 (t, 1H); 3.37 (m,2H); 2.49 (m, 2H partially covered by the DMSO peak); 1.55 (m, 2H).

Example 26 Compound No. 29 in Table 2N-[4-Methoxy-6-(pyrrolidin-1-yl)-pyridin-3-yl]-5-trifluoromethyl-1-[(4-pyridinyl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxamide26.1 4-Methoxy-5-nitro-2-(pyrrolidin-1-yl)pyridine

The method described in Stage 12.1 is followed, starting from 5.4 g(28.64 mmol) of 2-chloro-4-methoxy-5-nitropyridine (WO2003/080610) and4.53 g (63 mmol) of pyrrolidine. The product obtained is, in this case,purified by chromatography on a silica column, eluting with a mixture ofheptane and ethyl acetate. In this way we isolate 3 g of the expectedproduct.

¹H NMR (DMSO D₆), δ (ppm): 8.98 (s, 1H); 5.79 (s, 1H); 4.07 (s, 3H);3.65 (m, 4H); 2.17 (m, 4H).

26.2 5-Amino-4-methoxy-2-(pyrrolidin-1-yl)pyridine (Amine Vd)

The method described in Stage 12.2 is followed, starting from 1.5 g(6.72 mmol) of 4-methoxy-5-nitro-2-(pyrrolidin-1-yl)-pyridine, obtainedin Stage 6.1, and 0.15 g of palladium on charcoal at 10%. We thus obtain1.25 g of the expected product.

¹H NMR (DMSO D₆), δ (ppm): 7.16 (s, 1H); 6.61 (s, 1H); 4.52 (broadenedpeak, 2H); 3.71 (s, 3H); 3.29 (m, 4H); 1.81 (m, 4H).

26.3N-[4-Methoxy-6-(pyrrolidin-1-yl)pyridin-3-yl]-5-trifluoromethyl-1-[(4-pyridyl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxamide(Compound No. 29 in Table 2)

The method described in Example 12.3 is followed, starting from5-amino-4-methoxy-2-(pyrrolidin-1-yl)pyridine, prepared in the precedingstage, and5-trifluoromethyl-1-[(4-pyridyl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxylicacid prepared in Stage 9.2.

m.p.=222-224° C.

¹H NMR (DMSO D₆), δ (ppm): 9.86 (s, 1H); 8.79 (s, 1H); 8.71 (s. 1H);8.45 (d, 2H); 7.85 (s, 1H); 7.59 (s, 1H); 7.02 (d, 2H); 6.01 (s, 1H);5.95 (s, 1H); 4.38 (s, 3H); 3.39 (m, 4H); 1.93 (m, 4H)

Example 27 Compound No. 124 in Table 2N-[6-(3-Hydroxyazetidin-1-yl)-pyridin-3-yl]-1-(3-methoxybenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamidetrifluoroacetate (1:1) 27.11-(3-Methoxybenzyl)-1H-pyrrolo[2,3-b]pyridine-2-ethyl carboxylate

0.089 mL (0.45 mmol) of diisopropyl azodicarboxylate is added dropwiseunder argon at 20° C., to a mixture of 260 mg (0.6 mmol) of supportedtriphenylphosphine (Argonaut PS—PPh₃, loading 2.3 mmol/g), 57 mg (0.3mmol) of 1H-pyrrolo[2,3-b]pyridine-2-ethyl carboxylate (WO07/010,138)and 62 mg (0.45 mmol) of 3-methoxybenzyl alcohol in 2.5 mL oftetrahydrofuran. The reactor is then sealed and the mixture is stirredfor 3 days at 20° C. After this time, the reaction mixture is filtered,the solid residue is washed with 5 mL of tetrahydrofuran and thefiltrate is concentrated at reduced pressure to give the expectedproduct, which is used as it is in the rest of the synthesis.

27.2 1-(3-Methoxybenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid

A mixture of 1-(3-methoxybenzyl)-1H-pyrrolo[2,3-b]pyridine-2-ethylcarboxylate obtained in the preceding stage and 0.195 mL (0.39 mmol) of2N sodium hydroxide in 5 mL of ethanol and 1 mL of water is heated in asealed tube at 70° C. for 2 h. After this time, the reaction mixture isconcentrated at reduced pressure, and is then taken up in 2 mL ofdimethylformamide and 0.03 mL of trifluoroacetic acid. The solution isfiltered, and is then chromatographed on a reverse-phase HPLC column. Inthis way we isolate 33.4 mg of the expected product.

27.3N-[6-(3-Hydroxyazetidin-1-yl)pyridin-3-yl]-1-(3-methoxybenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamidetrifluoroacetate (1:1) (compound No. 124 in Table 2)

According to a method similar to that described in Stage 12.3, startingfrom 0.0167 g (0.59 mmol) of1-(3-methoxybenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid,described in the preceding stage, and 0.0149 g (0.09 mmol) of3-amino-6-(3-hydroxyazetidin-1-yl)pyridine, prepared in Stage 14.2, weobtain 0.013 g of the expected product.

LCMS: [MH]⁺=430

¹H NMR (DMSO D₆), δ (ppm): 10.59 (s, 1H); 8.45 (d, 1H); 8.4 (s, 1H);8.21 (d, 1H); 8.01 (d, 1H); 7.39 (s, 1H); 7.26 (m, 1H); 7.12 (dxd, 1H);6.75 (m, 2H); 6.52 (m, 2H); 5.89 (s, 2H); 4.62 (m, 1H); 4.32 (m, 2H);3.86 (m, 2H); 3.62 (s, 3H).

According to a method similar to that described in Example 27, 128 othercompounds were prepared and characterized by their mass peak in LC-MS inTables 2, 3 and 4. As examples, the ¹H NMR spectra of some of theseproducts are described below:

N-[6-(Azetidin-1-yl)-pyridin-3-yl]-1-(2-fluorobenzyl)-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamidetrifluoroacetate (1:1) (compound No. 43 in Table 2)

LCMS: [MH]⁺=470

¹H NMR (DMSO D₆), δ (ppm): 10.7 (s, 1H); 8.79 (d, 2H); 8.34 (s, 1H);7.99 (d, 1H); 7.59 (s, 1H); 7.28 (m, 1H); 7.19 (m, 1H); 7.02 (t, 1H);6.7 (m, 2H); 6 (s, 2H); 4.12 (m, 4H); 2.4 (m, 2H).

N-[6-(Azetidin-1-yl)pyridin-3-yl]-1-(4-fluorobenzyl)-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamidetrifluoroacetate (1:1) (compound No. 44 in Table 2)

LCMS: [MH]⁺=470

¹H NMR (DMSO D₆), δ (ppm): 10.7 (s, 1H); 8.82 (s, 1H); 8.76 (s, 1H);8.49 (s, 1H); 8.02 (s, 1H); 7.58 (s, 1H); 7.19 (m, 2H); 7.09 (m, 2H);6.75 (d, 1H); 5.93 (s, 2H); 4.12 (m, 4H); 2.41 (m, 2H).

N-[6-(Azetidin-1-yl)pyridin-3-yl]-1-(3-trifluoromethylbenzyl)-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamidetrifluoroacetate (1:1) (compound No. 45 in Table 2)

LCMS: [MH]⁺=520

¹H NMR (DMSO D₆), δ (ppm): 10.7 (s, 1H); 8.85 (s, 1H); 8.78 (s, 1H);8.38 (s, 1H); 8 (broadened peak, 1H); 7.6 (m, 3H); 7.51 (m, 1H); 7.37(m, 1H); 6.72 (broadened peak, 1H); 6.03 (s, 2H); 4.11 (m, 4H); 2.39 (m,2H).

N-[6-(Azetidin-1-yl)pyridin-3-yl]-1-(4-methylbenzyl)-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamidetrifluoroacetate (1:1) (compound No. 46 in Table 2)

LCMS: [MH]⁺=466

¹H NMR (DMSO D₆), δ (ppm): 10.61 (s, 1H); 8.82 (s, 1H); 8.73 (s, 1H);8.39 (s, 1H); 8 (broadened peak, 1H); 7.52 (s, 1H); 7.04 (m, 4H); 6.71(broadened peak, 1H); 5.91 (s, 2H); 4.11 (m, 4H); 2.4 (m, 2H); 2.21 (s,3H).

N-[6-(Azetidin-1-yl)pyridin-3-yl]-1-(3-methoxybenzyl)-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamidetrifluoroacetate (1:1) (compound No. 48 in Table 2)

LCMS: [MH]⁺=482

¹H NMR (DMSO D₆), δ (ppm): 10.7 (s, 1H); 8.81 (s, 1H); 8.75 (s, 1H);8.39 (s, 1H); 8 (broadened peak, 1H); 7.55 (s, 1H); 7.17 (t, 1H); 6.79(dxd, 1H); 6.75 (broadened peak, 1H); 6.67 (s, 1H); 6.63 (d, 1H); 5.94(s, 2H); 4.11 (m, 4H); 3.65 (s, 3H); 2.41 (m, 2H).

N-[6-(Azetidin-1-yl)-pyridin-3-yl]-1-(3-chlorobenzyl)-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamidetrifluoroacetate (1:1) (compound No. 49 in Table 2)

LCMS: [MH]⁺=486

¹H NMR (DMSO D₆), δ (ppm): 10.71 (s, 1H); 8.84 (s, 1H); 8.78 (s, 1H);8.39 (s, 1H); 8 (broadened peak, 1H); 7.6 (s, 1H); 7.3 (m, 2H); 7.2 (d,1H); 7.08 (m, 1H); 6.72 (broadened peak, 1H); 5.94 (s, 2H); 4.1 (m, 4H);2.4 (m, 2H).

N-[6-(Azetidin-1-yl)-pyridin-3-yl]-1-(3-trifluoromethoxybenzyl)-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamidetrifluoroacetate (1:1) (compound No. 50 in Table 2)

LCMS: [MH]⁺=536

¹H NMR (DMSO D₆), δ (ppm): 10.71 (s, 1H); 8.83 (s, 1H); 8.78 (s, 1H);8.38 (s, 1H); 8 (broadened peak, 1H); 7.6 (s, 1H); 7.4 (t, 1H); 7.25 (d,1H); 7.16 (s, 1H); 7.11 (d, 1H); 6.73 (broadened peak, 1H); 6 (s, 2H);4.12 (m, 4H); 2.41 (m, 2H).

N-[6-(Azetidin-1-yl)-pyridin-3-yl]-1-(4-methoxybenzyl)-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamidetrifluoroacetate (1:1) (compound No. 51 in Table 2)

LCMS: [MH]⁺=482

¹H NMR (DMSO D₆), δ (ppm): 10.6 (s, 1H); 8.82 (s, 1H); 8.71 (s, 1H);8.39 (s, 1H); 8.01 (broadened peak, 1H); 7.51 (s, 1H); 7.11 (d, 2H);6.82 (d, 1H); 6.71 (broadened peak, 1H); 5.9 (s, 2H); 4.12 (m, 4H); 3.67(s, 3H); 2.41 (m, 2H).

N-[6-(Azetidin-1-yl)-pyridin-3-yl]-1-(4-methoxybenzyl)-5-fluoro-1H-pyrrolo[2,3-b]pyridine-2-carboxamidetrifluoroacetate (1:1) (compound No. 62 in Table 2)

LCMS: [MH]⁺=432

¹H NMR (DMSO D₆), δ (ppm): 10.55 (s, 1H); 8.49 (s, 1H); 8.39 (s, 1H);8.14 (dxd, 1H); 8.01 (broadened peak, 1H); 7.35 (s, 1H); 7.1 (d, 2H);6.8 (d, 2H); 6.72 (broadened peak, 1H); 5.82 (s, 2H); 4.12 (m, 4H); 3.68(s, 3H); 2.4 (m, 2H).

N-[6-(Azetidin-1-yl)-pyridin-3-yl]-1-(3-trifluoromethylbenzyl)-6-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamidetrifluoroacetate (1:1) (compound No. 67 in Table 2)

LCMS: [MH]⁺=520

¹H NMR (DMSO D₆), δ (ppm): 10.7 (s, 1H); 8.53 (d, 1H); 8.39 (s, 1H);7.98 (broadened peak, 1H); 7.77 (d, 1H); 7.71 (s, 1H); 7.61 (d, 1H);7.55 (s, 1H); 7.49 (m, 2H); 6.71 (broadened peak, 1H); 5.98 (s, 2H);4.12 (m, 4H); 2.39 (m, 2H).

N-[6-(Azetidin-1-yl)-pyridin-3-yl]-1-(4-methylbenzyl)-6-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamidetrifluoroacetate (1:1) (compound No. 68 in Table 2)

LCMS: [MH]⁺=466

¹H NMR (DMSO D₆), δ (ppm): 10.68 (s, 1H); 8.51 (d, 1H); 8.39 (s, 1H);7.98 (broadened peak, 1H); 7.71 (d, 1H); 7.5 (s, 1H); 7.05 (m, 4H); 6.75(broadened peak, 1H); 5.87 (s, 2H); 4.12 (m, 4H); 2.39 (m, 2H); 2.2 (s,3H).

N-[6-(Azetidin-1-yl)-pyridin-3-yl]-1-(3-chlorobenzyl)-6-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamidetrifluoroacetate (1:1) (compound No. 71 in Table 2)

LCMS: [MH]⁺=486

¹H NMR (DMSO D₆), δ (ppm): 10.7 (s, 1H); 8.54 (d, 1H); 8.36 (s, 1H);7.98 (broadened peak, 1H); 7.73 (d, 1H); 7.55 (s, 1H); 7.29 (m, 3H);7.09 (m, 1H); 6.72 (broadened peak, 1H); 5.91 (s, 2H); 4.1 (m, 4H); 2.4(m, 2H).

N-[6-(Azetidin-1-yl)-pyridin-3-yl]-1-benzyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamidetrifluoroacetate (1:1) (compound No. 75 in Table 2)

LCMS: [MH]⁺=384

¹H NMR (DMSO D₆), δ (ppm): 10.5 (s, 1H); 8.49 (d, 1H); 8.38 (s, 1H);8.22 (d, 1H); 8.01 (broadened peak, 1H); 7.41 (s, 1H); 7.22 (m, 4H);7.09 (m, 2H); 6.72 (broadened peak, 1H); 5.93 (s, 2H); 4.12 (m, 4H);2.39 (m, 2H).

N-[6-(Azetidin-1-yl)-pyridin-3-yl]-1-(3-trifluoromethylbenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamidetrifluoroacetate (1:1) (compound No. 78 in Table 2)

LCMS: [MH]⁺=452

¹H NMR (DMSO D₆), δ (ppm): 10.6 (s, 1H); 8.49 (d, 1H); 8.39 (s, 1H);8.27 (d, 1H); 8.02 (broadened peak, 1H); 7.59 (d, 1H); 7.53 (s, 1H);7.48 (m, 2H); 7.39 (d, 1H); 7.29 (m, 1H); 6.77 (broadened peak, 1H); 6(s, 2H); 4.12 (m, 4H); 2.41 (m, 2H).

N-[6-(Azetidin-1-yl)-pyridin-3-yl]-1-(3-methoxybenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamidetrifluoroacetate (1:1) (compound No. 81 in Table 2)

LCMS: [MH]⁺=414

¹H NMR (DMSO D₆), δ (ppm): 10.5 (s, 1H); 8.47 (d, 1H); 8.39 (s, 1H);8.21 (d, 1H); 7.98 (broadened peak, 1H); 7.39 (s, 1H); 7.27 (dxd, 1H);7.13 (m, 1H); 6.78 (m, 1H); 6.7 (broadened peak, 1H); 6.62 (m, 2H); 5.91(s, 2H); 4.09 (m, 4H); 3.62 (s, 3H); 2.4 (m, 2H).

N-[6-(Azetidin-1-yl)-pyridin-3-yl]-1-(4-methoxylbenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamidetrifluoroacetate (1:1) (compound No. 84 in Table 2)

LCMS: [MH]⁺=414

¹H NMR (DMSO D₆), δ (ppm): 10.31 (s, 1H); 8.47 (d, 1H); 8.38 (s, 1H);8.19 (d, 1H); 7.91 (broadened peak, 1H); 7.32 (s, 1H); 7.23 (dxd, 1H);7.1 (m, 2H); 6.78 (m, 2H); 6.57 (broadened peak, 1H); 5.85 (s, 2H); 4.01(m, 4H); 3.67 (s, 3H); 2.35 (m, 2H).

N-[6-(3-Hydroxyazetidin-1-yl)pyridin-3-yl]-5-fluoro-1-(3-trifluoromethoxybenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamidetrifluoroacetate (1:1) (compound No. 115 in Table 2)

LCMS: [MH]⁺=502

¹H NMR (DMSO D₆), δ (ppm): 10.51 (s, 1H); 8.48 (s, 1H); 8.35 (s, 1H);8.19 (d, 1H); 7.92 (broadened peak, 1H); 7.41 (m, 2H); 7.21 (d, 1H);7.12 (m, 2H); 6.63 (m, 1H); 5.91 (s, 2H); 4.6 (m, 1H); 4.23 (m, 2H);3.78 (m, 2H).

N-[6-(3-Hydroxyazetidin-1-yl)-pyridin-3-yl]-5-fluoro-1-(4-methoxybenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamidetrifluoroacetate (1:1) (compound No. 116 in Table 2)

LCMS: [MH]⁺=448

¹H NMR (DMSO D₆), δ (ppm): 10.4 (s, 1H); 8.47 (s, 1H); 8.36 (s, 1H);8.11 (dxd, 1H); 7.89 (broadened peak, 1H); 7.31 (s, 1H); 7.1 (d, 2H);6.8 (d, 2H); 6.51 (m, 1H); 5.81 (s, 2H); 4.58 (m, 1H); 4.2 (m, 2H); 3.7(m, 2H); 3.67 (s, 3H).

N-[6-(3-Hydroxyazetidin-1-yl)-pyridin-3-yl]-5-fluoro-1-(3-chloro-5-trifluoromethylbenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamidetrifluoroacetate (1:1) (compound No. 117 in Table 2)

LCMS: [MH]⁺=520

¹H NMR (DMSO D₆), δ (ppm): 10.55 (s, 1H); 8.49 (s, 1H); 8.34 (s, 1H);8.2 (d, 1H); 7.9 (broadened peak, 1H); 7.73 (s, 1H); 7.51 (s, 1H); 7.45(m, 2H); 6.61 (m, 1H); 5.91 (s, 2H); 4.6 (m, 1H); 4.25 (m, 2H); 3.78 (m,2H).

N-[6-(3-Hydroxyazetidin-1-yl)-pyridin-3-yl]-1-(3-chlorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamidetrifluoroacetate (1:1) (compound No. 125 in Table 2)

LCMS: [MH]⁺=434

¹H NMR (DMSO D₆), δ (ppm): 10.41 (s, 1H); 8.47 (d, 1H); 8.35 (s, 1H);8.22 (d, 1H); 7.92 (broadened peak, 1H); 7.41 (s, 1H); 7.29 (m, 3H);7.12 (s, 1H); 7.05 (d, 1H); 6.62 (m, 1H); 5.91 (s, 2H); 4.61 (m, 1H);4.25 (m, 2H); 3.78 (m, 2H).

N-[6-(Azetidin-1-yl)-pyridin-3-yl]-1-benzyl-5-trifluoromethyl-1H-pyrrolo[3,2-b]pyridine-2-carboxamidetrifluoroacetate (1:1) (compound No. 129 in Table 3)

LCMS: [MH]⁺=452

¹H NMR (DMSO D₆), δ (ppm): 10.72 (s, 1H); 8.4 (s, 1H); 8.32 (d, 1H);8.01 (broadened peak, 1H); 7.78 (d, 1H); 7.61 (s, 1H); 7.26 (m, 3H);7.11 (m, 2H); 6.72 (broadened peak, 1H); 5.95 (s, 2H); 4.12 (m, 4H);2.41 (m, 2H).

N-[6-(Azetidin-1-yl)-pyridin-3-yl]-1-(4-fluorobenzyl)-5-trifluoromethyl-1H-pyrrolo[3,2-b]pyridine-2-carboxamidetrifluoroacetate (1:1) (compound No. 131 in Table 3)

LCMS: [MH]⁺=470

¹H NMR (DMSO D₆), δ (ppm): 10.71 (s, 1H); 8.37 (m, 2H); 8 (broadenedpeak, 1H); 7.8 (d, 1H); 7.61 (s, 1H); 7.15 (m, 4H); 6.72 (broadenedpeak, 1H); 5.91 (s, 2H); 4.12 (m, 4H); 2.41 (m, 2H).

N-[6-(Azetidin-1-yl)-pyridin-3-yl]-1-(3-methylbenzyl)-5-trifluoromethyl-1H-pyrrolo[3,2-b]pyridine-2-carboxamidetrifluoroacetate (1:1) (compound No. 134 in Table 3)

LCMS: [MH]⁺=466

¹H NMR (DMSO D₆), δ (ppm): 10.75 (s, 1H); 8.39 (s, 1H); 8.31 (d, 1H); 8(broadened peak, 1H); 7.78 (d, 1H); 7.59 (s, 1H); 7.15 (m, 1H); 7.04 (d,1H); 6.96 (s, 1H); 6.84 (d, 1H); 6.72 (broadened peak, 1H); 5.9 (s, 2H);4.12 (m, 4H); 2.4 (m, 2H); 2.2 (s, 3H).

N-[6-(Azetidin-1-yl)-pyridin-3-yl]-1-(3-methoxybenzyl)-5-trifluoromethyl-1H-pyrrolo[3,2-b]pyridine-2-carboxamidetrifluoroacetate (1:1) (compound No. 135 in Table 3)

LCMS: [MH]⁺=482

¹H NMR (DMSO D₆), δ (ppm): 10.75 (s, 1H); 8.4 (s, 1H); 8.31 (d, 1H); 8(broadened peak, 1H); 7.78 (d, 1H); 7.6 (s, 1H); 7.19 (m, 1H); 6.8 (dxd,1H); 6.72 (m, 2H); 6.61 (d, 1H); 5.91 (s, 2H); 4.12 (m, 4H); 3.65 (s,3H); 2.41 (m, 2H).

N-[6-(Azetidin-1-yl)-pyridin-3-yl]-1-(4-methoxybenzyl)-5-trifluoromethyl-1H-pyrrolo[3,2-b]pyridine-2-carboxamidetrifluoroacetate (1:1) (compound No. 138 in Table 3)

LCMS: [MH]⁺=482

¹H NMR (DMSO D₆), δ (ppm): 10.7 (s, 1H); 8.4 (s, 1H); 8.35 (d, 1H); 8.02(broadened peak, 1H); 7.78 (d, 1H); 7.58 (s, 1H); 7.11 (d, 2H); 6.84 (d,2H); 6.75 (broadened peak, 1H); 5.87 (s, 2H); 4.12 (m, 4H); 3.69 (s,3H); 2.39 (m, 2H).

N-[6-(3-Hydroxyazetidin-1-yl)-pyridin-3-yl]-1-(3-trifluoromethylbenzyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamidetrifluoroacetate (1:1) (compound No. 164 in Table 4)

LCMS: [MH]⁺=468

¹H NMR (DMSO D₆), δ (ppm): 10.8 (s, 1H); 9.51 (s, 1H); 8.92 (s, 1H);8.88 (s, 1H); 8.44 (d, 1H); 8.32 (m, 2H); 7.85 (broadened peak, 1H);7.63 (m, 2H); 7.53 (m, 1H); 7.39 (d, 1H); 6.51 (broadened peak, 1H);6.09 (s, 2H); 4.58 (m, 1H); 4.2 (m, 2H); 3.71 (m, 2H).

N-[6-(3-Hydroxyazetidin-1-yl)-pyridin-3-yl]-1-(4-methylbenzyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamidetrifluoroacetate (1:1) (compound No. 165 in Table 4)

LCMS: [MH]⁺=414

¹H NMR (DMSO D₆), δ (ppm): 10.75 (s, 1H); 8.93 (s, 1H); 8.9 (s, 1H);8.35 (m, 3H); 7.88 (broadened peak, 1H); 7.59 (s, 1H); 7.09 (m, 4H);6.51 (broadened peak, 1H); 5.95 (s, 2H); 4.59 (m, 1H); 4.2 (m, 2H); 3.72(m, 2H); 2.22 (s, 3H).

The following Tables 2, 3 and 4 illustrate the chemical structures andthe physical properties of some compounds of general formula (I)according to the invention.

In these tables:

-   -   the column “MP (° C.) or [MH]⁺” shows, respectively, either the        melting points of the products in degrees Celsius (° C.), or        their mass peak in LC-MS;    -   in the column “Salt/base”, “-” represents a compound in the form        of free base, whereas “HCl” represents a compound in the form of        hydrochloride and “TFA” represents a compound in the form of        trifluoroacetate; the ratio in parentheses is the (acid:base)        ratio;    -   “CH₃” corresponds to a methyl group, “Et” corresponds to an        ethyl group,    -   “CF₃” corresponds to a trifluoromethyl group, “NC₄H₈” to a        pyrrolidin-1-yl group.

TABLE 2

MP (° C.) No. X Y Z₁, Z₂, Z₃, Z₄ Z salt or [MH]⁺  1 5-CF₃ 3-fluorophenylCH, CH, CH, N NHCH₃ — 252-254  2 5-CF₃ 3-fluorophenyl CH, C(CH₃), CH,N(CH₃)₂ HCl 252-257 N 1:1  3 5-CF₃ 3-fluorophenyl C(CH₃), CH, CH,N(CH₃)₂ HCl 242-247 N 1:1  4 5-CF₃ 3-fluorophenyl CH, C(CF₃), CH,N(CH₃)₂ HCl 213-218 N 1:1  5 5-F 3-fluorophenyl CH, CH, CH, N NC₄H₈ —239-240 HCl 241-242 2:3  6 5-CF₃ 3-fluorophenyl CH, CH, CH, N NC₄H₈ —234-236  7 5-CF₃ 3-fluorophenyl N, CH, CH, N NC₄H₈ — 182-183  8 5-CF₃3-fluorophenyl CH, CH, N, N N(CH₃)₂ — 224-226  9 5-CF₃ pyridin-4-yl CH,CH, CH, N NC₄H₈ — 244-245  10 5-CF₃ 3-fluorophenyl CH, CH, CH, NNHCH(CH₃)₂ — 210-212  11 5-CF₃ 3-fluorophenyl CH, CH, CH, N 3-hydroxy- —233-235 pyrrolidinyl  12 5-CF₃ 3-fluorophenyl CH, CH, CH, N3,3-difluoro- — 211-213 pyrrolidinyl  13 5-CF₃ 3-fluorophenyl CH, CH,CH, N N(CH₃)₂ — 233-235  14 5-CF₃ 3-fluorophenyl CH, CH, CH, N cis-2,5-— [MH]⁺ = dimethyl- 512 pyrrolidinyl  15 5-CF₃ 3-fluorophenyl CH, CH,CH, N azetidinyl — 243-244 HCl 230-235 1:1  17 5-CF₃ 3-fluorophenyl CH,CH, CH, N (S)-prolinyl — 235-237  18 5-CF₃ 3-fluorophenyl CH, CH, CH, N(S)-prolinyl ter- — 106-108 butyl ester  19 5-CF₃ 3-fluorophenyl CH, CH,CH, N 3,3-difluoro — 222-224 azetidinyl  20 5-CF₃ 3-fluorophenyl CH, CH,CH, N 3-hydroxy — 221-223 azetidinyl  21 5-CF₃ 3-fluorophenyl C(CH₃),CH, CH, N(CH₃)₂ — 222-223 N  22 6-CF₃ 3-fluorophenyl C(CH₃), CH, CH,NC₄H₈ — 202-203 N  23 5-CF₃ 3-fluorophenyl CH, CH, CH, N 3-methoxy —154-156 pyrrolidinyl  24 5-CF₃ pyridin-4-yl C(CH₃), CH, CH, N(CH₃)₂ —241-242 N  25 5-CF₃ 3-fluorophenyl C(CH₃), CH, CH, NC₄H₈ — 225-226 N  266-CF₃ pyridin-4-yl C(CH₃), CH, CH, NC₄H₈ — 240-241 N  27 5-CF₃pyridin-4-yl C(CH₃), CH, CH, NC₄H₈ — 251-252 N  28 5-CF₃ pyridin-4-ylC(CH₃), CH, CH, NHCH₃ — 230-231 N  29 5-CF₃ pyridin-4-yl C(OCH₃), CH,CH, NC₄H₈ — 222-224 N  30 5-CF₃ pyridin-4-yl CH, CH, CH, N azetidinyl —233-235  31 5-CF₃ 3-fluorophenyl CH, CH, CH, N NHC(O)CH₃ — 282-284  325-CF₃ 3-fluorophenyl CH, CH, CH, N NH₂ — 230-232  33 6-CF₃3-fluorophenyl CH, CH, CH, N NC₄H₈ — 204-205  34 5-CF₃ 3-fluorophenylC(CF₃), CH, CH, NC₄H₈ — 207-208 N  35 5-CF₃ 3-fluorophenyl CH, C(F), CH,N N(CH₃)₂ — 199-200  36 5-CF₃ 3-fluorophenyl CH, N, CH, N N(CH₃)₂ —236-238  37 5-CF₃ 3-fluorophenyl CH, CH, CH, N 3-azabicyclo — 172-174[3,2,0]heptyl  38 5-CF₃ 3-fluorophenyl CH, CH, CH, N 3-azabicyclo —212-214 [3,1,0]hexyl  39 5-F 3-fluorophenyl CH, CH, CH, N 3-azabicyclo —222-224 [3,1,0]hexyl  40 5-CF₃ 3-fluorophenyl CH, CH, CH, N NH(CH₂)₂CO₂H— 196-199  41 5-CF₃ 3-fluorophenyl CH, CH, CH, N NH(CH₂)₃OH — 207-210 42 5-CF₃ phenyl CH, CH, CH, N azetidinyl TFA [MH]⁺ 452 1:1  43 5-CF₃2-fluorophenyl CH, CH, CH, N azetidinyl TFA [MH]⁺ 470 1:1  44 5-CF₃4-fluorophenyl CH, CH, CH, N azetidinyl TFA [MH]⁺ 470 1:1  45 5-CF₃3-trifluoro CH, CH, CH, N azetidinyl TFA [MH]⁺ 520 methylphenyl 1:1  465-CF₃ 4- CH, CH, CH, N azetidinyl TFA [MH]⁺ 466 methylphenyl 1:1  475-CF₃ 3- CH, CH, CH, N azetidinyl TFA [MH]⁺ 466 methylphenyl 1:1  485-CF₃ 3-methoxy CH, CH, CH, N azetidinyl TFA [MH]⁺ 482 phenyl 1:1  495-CF₃ 3-chlorophenyl CH, CH, CH, N azetidinyl TFA [MH]⁺ 486 1:1  505-CF₃ 3-trifluoro CH, CH, CH, N azetidinyl TFA [MH]⁺ 536 methoxyphenyl1:1  51 5-CF₃ 4- CH, CH, CH, N azetidinyl TFA [MH]⁺ 482 methoxyphenyl1:1  52 5-CF₃ 3-chloro-5- CH, CH, CH, N azetidinyl TFA [MH]⁺ 554trifluoro 1:1 methylphenyl  53 5-F phenyl CH, CH, CH, N azetidinyl TFA[MH]⁺ 402 1:1  54 5-F 2-fluorophenyl CH, CH, CH, N azetidinyl TFA [MH]⁺420 1:1  55 5-F 4-fluorophenyl CH, CH, CH, N azetidinyl TFA [MH]⁺ 4201:1  56 5-F 3-trifluoro CH, CH, CH, N azetidinyl TFA [MH]⁺ 470methylphenyl 1:1  57 5-F 4- CH, CH, CH, N azetidinyl TFA [MH]⁺ 416methylphenyl 1:1  58 5-F 3- CH, CH, CH, N azetidinyl TFA [MH]⁺ 416methylphenyl 1:1  59 5-F 3-methoxy CH, CH, CH, N azetidinyl TFA [MH]⁺432 phenyl 1:1  60 5-F 3-chlorophenyl CH, CH, CH, N azetidinyl TFA [MH]⁺436 1:1  61 5-F 3-trifluoro CH, CH, CH, N azetidinyl TFA [MH]⁺ 486methoxyphenyl 1:1  62 5-F 4-methoxy CH, CH, CH, N azetidinyl TFA [MH]⁺432 phenyl 1:1  63 5-F 3-chloro-5- CH, CH, CH, N azetidinyl TFA [MH]⁺504 trifluoro 1:1 methylphenyl  64 6-CF₃ phenyl CH, CH, CH, N azetidinylTFA [MH]⁺ 452 1:1  65 6-CF₃ 2-fluorophenyl CH, CH, CH, N azetidinyl TFA[MH]⁺ 470 1:1  66 6-CF₃ 4-fluorophenyl CH, CH, CH, N azetidinyl TFA[MH]⁺ 470 1:1  67 6-CF₃ 3-trifluoro CH, CH, CH, N azetidinyl TFA [MH]⁺520 methylphenyl 1:1  68 6-CF₃ 4- CH, CH, CH, N azetidinyl TFA [MH]⁺ 466methylphenyl 1:1  69 6-CF₃ 3- CH, CH, CH, N azetidinyl TFA [MH]⁺ 466methylphenyl 1:1  70 6-CF₃ 3-methoxy CH, CH, CH, N azetidinyl TFA [MH]⁺482 phenyl 1:1  71 6-CF₃ 3-chlorophenyl CH, CH, CH, N azetidinyl TFA[MH]⁺ 486 1:1  72 6-CF₃ 3-trifluoro CH, CH, CH, N azetidinyl TFA [MH]⁺536 methoxyphenyl 1:1  73 6-CF₃ 4-methoxy CH, CH, CH, N azetidinyl TFA[MH]⁺ 482 phenyl 1:1  74 6-CF₃ 3-chloro-5- CH, CH, CH, N azetidinyl TFA[MH]⁺ 554 trifluoro 1:1 methylphenyl  75 H phenyl CH, CH, CH, Nazetidinyl TFA [MH]⁺ 384 1:1  76 H 2-fluorophenyl CH, CH, CH, Nazetidinyl TFA [MH]⁺ 402 1:1  77 H 4-fluorophenyl CH, CH, CH, Nazetidinyl TFA [MH]⁺ 402 1:1  78 H 3-trifluoro CH, CH, CH, N azetidinylTFA [MH]⁺ 452 methylphenyl 1:1  79 H 4- CH, CH, CH, N azetidinyl TFA[MH]⁺ 398 methylphenyl 1:1  80 H 3- CH, CH, CH, N azetidinyl TFA [MH]⁺398 methylphenyl 1:1  81 H 3-methoxy CH, CH, CH, N azetidinyl TFA [MH]⁺414 phenyl 1:1  82 H 3-chlorophenyl CH, CH, CH, N azetidinyl TFA [MH]⁺418 1:1  83 H 3-trifluoro CH, CH, CH, N azetidinyl TFA [MH]⁺ 468methoxyphenyl 1:1  84 H 4-methoxy CH, CH, CH, N azetidinyl TFA [MH]⁺ 414phenyl 1:1  85 H 3-chloro-5- CH, CH, CH, N azetidinyl TFA [MH]⁺ 486trifluoro 1:1 methylphenyl  86 5-CF₃ 2-fluorophenyl CH, CH, CH, N3-hydroxy TFA [MH]⁺ 486 azetidinyl 1:1  87 5-CF₃ 4-fluorophenyl CH, CH,CH, N 3-hydroxy TFA [MH]⁺ 486 azetidinyl 1:1  88 5-CF₃ 3-trifluoro CH,CH, CH, N 3-hydroxy TFA [MH]⁺ 536 methylphenyl azetidinyl 1:1  89 5-CF₃4- CH, CH, CH, N 3-hydroxy TFA [MH]⁺ 482 methylphenyl azetidinyl 1:1  905-CF₃ 3- CH, CH, CH, N 3-hydroxy TFA [MH]⁺ 482 methylphenyl azetidinyl1:1  91 5-CF₃ 3-methoxy CH, CH, CH, N 3-hydroxy TFA [MH]⁺ 498 phenylazetidinyl 1:1  92 5-CF₃ 3-chlorophenyl CH, CH, CH, N 3-hydroxy TFA[MH]⁺ 502 azetidinyl 1:1  93 5-CF₃ 3-trifluoro CH, CH, CH, N 3-hydroxyTFA [MH]⁺ 552 methoxyphenyl azetidinyl 1:1  94 5-CF₃ 4-methoxy CH, CH,CH, N 3-hydroxy TFA [MH]⁺ 498 phenyl azetidinyl 1:1  95 5-CF₃3-chloro-5- CH, CH, CH, N 3-hydroxy TFA [MH]⁺ 570 trifluoro azetidinyl1:1 methylphenyl  96 6-CF₃ phenyl CH, CH, CH, N 3-hydroxy TFA [MH]⁺ 468azetidinyl 1:1  97 6-CF₃ 2-fluorophenyl CH, CH, CH, N 3-hydroxy TFA[MH]⁺ 486 azetidinyl 1:1  98 6-CF₃ 4-fluorophenyl CH, CH, CH, N3-hydroxy TFA [MH]⁺ 486 azetidinyl 1:1  99 6-CF₃ 3-trifluoro CH, CH, CH,N 3-hydroxy TFA [MH]⁺ 536 methylphenyl azetidinyl 1:1 100 6-CF₃ 4- CH,CH, CH, N 3-hydroxy TFA [MH]⁺ 482 methylphenyl azetidinyl 1:1 101 6-CF₃3- CH, CH, CH, N 3-hydroxy TFA [MH]⁺ 482 methylphenyl azetidinyl 1:1 1026-CF₃ 3- CH, CH, CH, N 3-hydroxy TFA [MH]⁺ 498 methoxyphenyl azetidinyl1:1 103 6-CF₃ 3-chlorophenyl CH, CH, CH, N 3-hydroxy TFA [MH]⁺ 502azetidinyl 1:1 104 6-CF₃ 3-trifluoro CH, CH, CH, N 3-hydroxy TFA [MH]⁺552 methoxyphenyl azetidinyl 1:1 105 6-CF₃ 4- CH, CH, CH, N 3-hydroxyTFA [MH]⁺ 498 methoxyphenyl azetidinyl 1:1 106 6-CF₃ 3-chloro-5- CH, CH,CH, N 3-hydroxy TFA [MH]⁺ 570 trifluoro azetidinyl 1:1 methylphenyl 1075-F phenyl CH, CH, CH, N 3-hydroxy TFA [MH]⁺ 418 azetidinyl 1:1 108 5-F2-fluorophenyl CH, CH, CH, N 3-hydroxy TFA [MH]⁺ 436 azetidinyl 1:1 1095-F 4-fluorophenyl CH, CH, CH, N 3-hydroxy TFA [MH]⁺ 436 azetidinyl 1:1110 5-F 3-trifluoro CH, CH, CH, N 3-hydroxy TFA [MH]⁺ 486 methylphenylazetidinyl 1:1 111 5-F 4- CH, CH, CH, N 3-hydroxy TFA [MH]⁺ 432methylphenyl azetidinyl 1:1 112 5-F 3- CH, CH, CH, N 3-hydroxy TFA [MH]⁺432 methylphenyl azetidinyl 1:1 113 5-F 3-methoxy CH, CH, CH, N3-hydroxy TFA [MH]⁺ 448 phenyl azetidinyl 1:1 114 5-F 3-chlorophenyl CH,CH, CH, N 3-hydroxy TFA [MH]⁺ 452 azetidinyl 1:1 115 5-F 3-trifluoro CH,CH, CH, N 3-hydroxy TFA [MH]⁺ 502 methoxyphenyl azetidinyl 1:1 116 5-F4-methoxy CH, CH, CH, N 3-hydroxy TFA [MH]⁺ 448 phenyl azetidinyl 1:1117 5-F 3-chloro-5- CH, CH, CH, N 3-hydroxy TFA [MH]⁺ 520 trifluoroazetidinyl 1:1 methylphenyl 118 H phenyl CH, CH, CH, N 3-hydroxy TFA[MH]⁺ 400 azetidinyl 1:1 119 H 2-fluorophenyl CH, CH, CH, N 3-hydroxyTFA [MH]⁺ 418 azetidinyl 1:1 120 H 4-fluorophenyl CH, CH, CH, N3-hydroxy TFA [MH]⁺ 418 azetidinyl 1:1 121 H 3-trifluoro CH, CH, CH, N3-hydroxy TFA [MH]⁺ 468 methylphenyl azetidinyl 1:1 122 H 4- CH, CH, CH,N 3-hydroxy TFA [MH]⁺ 414 methylphenyl azetidinyl 1:1 123 H 3- CH, CH,CH, N 3-hydroxy TFA [MH]⁺ 414 methylphenyl azetidinyl 1:1 124 H3-methoxy CH, CH, CH, N 3-hydroxy TFA [MH]⁺ 430 phenyl azetidinyl 1:1125 H 3-chlorophenyl CH, CH, CH, N 3-hydroxy TFA [MH]⁺ 434 azetidinyl1:1 126 H 3-trifluoro CH, CH, CH, N 3-hydroxy TFA [MH]⁺ 484methoxyphenyl azetidinyl 1:1 127 H 4-methoxy CH, CH, CH, N 3-hydroxy TFA[MH]⁺ 430 phenyl azetidinyl 1:1 128 H 3-chloro-5- CH, CH, CH, N3-hydroxy TFA [MH]⁺ 502 trifluoro azetidinyl 1:1 methylphenyl 171 5-CF₃3-fluorophenyl CH, CH, CH, N NH(CH₂)₂CO₂Et — [MH]⁺ 530 172 5-CF₃3-fluorophenyl CH, CH, CH, N 3-(methoxy) — 185-187 azetidinyl 173 5-CF₃3-fluorophenyl CH, CH, CH, N 3-(cyclopropyl — 201-203 methyloxy)azetidinyl

TABLE 3

Z₁, Z₂, No. X Y Z₃, Z₄ Z salt MP (° C.)  16 5-CF₃ 3-fluoro- CH, CH,NC₄H₈ — 219-220 phenyl CH, N 129 5-CF₃ phenyl CH, CH, azetidinyl TFA[MH]⁺ 452 CH, N 1:1 130 5-CF₃ 2-fluoro- CH, CH, azetidinyl TFA [MH]⁺ 470phenyl CH, N 1:1 131 5-CF₃ 4-fluoro- CH, CH, azetidinyl TFA [MH]⁺ 470phenyl CH, N 1:1 132 5-CF₃ 3-trifluoro CH, CH, azetidinyl TFA [MH]⁺ 520methylphenyl CH, N 1:1 133 5-CF₃ 4-methyl- CH, CH, azetidinyl TFA [MH]⁺466 phenyl CH, N 1:1 134 5-CF₃ 3-methyl- CH, CH, azetidinyl TFA [MH]⁺466 phenyl CH, N 1:1 135 5-CF₃ 3-methoxy- CH, CH, azetidinyl TFA [MH]⁺482 phenyl CH, N 1:1 136 5-CF₃ 3-chloro- CH, CH, azetidinyl TFA [MH]⁺486 phenyl CH, N 1:1 137 5-CF₃ 3-trifluoro CH, CH, azetidinyl TFA [MH]⁺536 methoxyphenyl CH, N 1:1 138 5-CF₃ 4-methoxy- CH, CH, azetidinyl TFA[MH]⁺ 482 phenyl CH, N 1:1 139 5-CF₃ 3-chloro-5- CH, CH, azetidinyl TFA[MH]⁺ 554 trifluoro CH, N 1:1 methylphenyl 140 5-CF₃ phenyl CH, CH,3-hydroxy TFA [MH]⁺ 468 CH, N azetidinyl 1:1 141 5-CF₃ 2-fluoro- CH, CH,3-hydroxy TFA [MH]⁺ 486 phenyl CH, N azetidinyl 1:1 142 5-CF₃ 4-fluoro-CH, CH, 3-hydroxy TFA [MH]⁺ 486 phenyl CH, N azetidinyl 1:1 143 5-CF₃3-trifluoro- CH, CH, 3-hydroxy TFA [MH]⁺ 536 methylphenyl CH, Nazetidinyl 1:1 144 5-CF₃ 4-methyl- CH, CH, 3-hydroxy TFA [MH]⁺ 482phenyl CH, N azetidinyl 1:1 145 5-CF₃ 3-methyl- CH, CH, 3-hydroxy TFA[MH]⁺ 482 phenyl CH, N azetidinyl 1:1 146 5-CF₃ 3-methoxy- CH, CH,3-hydroxy TFA [MH]⁺ 498 phenyl CH, N azetidinyl 1:1 147 5-CF₃ 3-chloro-CH, CH, 3-hydroxy TFA [MH]⁺ 502 phenyl CH, N azetidinyl 1:1 148 5-CF₃3-trifluoro CH, CH, 3-hydroxy TFA [MH]⁺ 552 methoxyphenyl CH, Nazetidinyl 1:1 149 5-CF₃ 4-methoxy- CH, CH, 3-hydroxy TFA [MH]⁺ 498phenyl CH, N azetidinyl 1:1 150 5-CF₃ 3-chloro-5- CH, CH, 3-hydroxy TFA[MH]⁺ 570 trifluoro CH, N azetidinyl 1:1 methylphenyl

TABLE 4

No. X Y Z₁, Z₂, Z₃, Z₄ Z salt MP (° C.) 151 H phenyl CH, CH, CH, Nazetidinyl TFA [MH]⁺ 384 1:1 152 H 2-fluorophenyl CH, CH, CH, Nazetidinyl TFA [MH]⁺ 402 1:1 153 H 4-fluorophenyl CH, CH, CH, Nazetidinyl TFA [MH]⁺ 402 1:1 154 H 3-trifluoro CH, CH, CH, N azetidinylTFA [MH]⁺ 452 methylphenyl 1:1 155 H 4- CH, CH, CH, N azetidinyl TFA[MH]⁺ 398 methylphenyl 1:1 156 H 3- CH, CH, CH, N azetidinyl TFA [MH]⁺398 methylphenyl 1:1 157 H 3-methoxy CH, CH, CH, N azetidinyl TFA [MH]⁺414 phenyl 1:1 158 H 3-chlorophenyl CH, CH, CH, N azetidinyl TFA [MH]⁺418 1:1 159 H 3-trifluoro CH, CH, CH, N azetidinyl TFA [MH]⁺ 468methoxyphenyl 1:1 160 H 3-chloro-5- CH, CH, CH, N azetidinyl TFA [MH]⁺486 trifluoro 1:1 methylphenyl 161 H phenyl CH, CH, CH, N 3-hydroxy TFA[MH]⁺ 400 azetidinyl 1:1 162 H 2-fluorophenyl CH, CH, CH, N 3-hydroxyTFA [MH]⁺ 418 azetidinyl 1:1 163 H 4-fluorophenyl CH, CH, CH, N3-hydroxy TFA [MH]⁺ 418 azetidinyl 1:1 164 H 3-trifluoro CH, CH, CH, N3-hydroxy TFA [MH]⁺ 468 methylphenyl azetidinyl 1:1 165 H 4- CH, CH, CH,N 3-hydroxy TFA [MH]⁺ 414 methylphenyl azetidinyl 1:1 166 H 3- CH, CH,CH, N 3-hydroxy TFA [MH]⁺ 414 methylphenyl azetidinyl 1:1 167 H3-methoxy CH, CH, CH, N 3-hydroxy TFA [MH]⁺ 430 phenyl azetidinyl 1:1168 H 3-chlorophenyl CH, CH, CH, N 3-hydroxy TFA [MH]⁺ 434 azetidinyl1:1 169 H 3-trifluoro CH, CH, CH, N 3-hydroxy TFA [MH]⁺ 484methoxyphenyl azetidinyl 1:1 170 H 3-chloro-5- CH, CH, CH, N 3-hydroxyTFA [MH]⁺ 502 trifluoro azetidinyl 1:1 methylphenyl

The compounds of the invention underwent pharmacological testing invitro and in vivo and this demonstrated that they are interesting assubstances with therapeutic effects.

The compounds of the invention also display characteristics ofsolubility in water, which favors good activity in vivo.

Test of Inhibition of the Current Induced by Capsaicin on the Rat DRG

Primary Culture of Rat Dorsal Root Ganglion (DRG) Cells:

The neurons of the DRG express the TRPV1 receptor naturally.

Primary cultures of DRG of neonate rats are prepared from 1-day-oldrats. Briefly, after dissection, the ganglia are trypsinized and thecells are dissociated mechanically by careful trituration. The cells areresuspended in Eagle's basic culture medium containing 10% of fetal calfserum, 25 mM KCl, 2 mM glutamine, 100 μg/ml gentamicin and 50 ng/ml ofNGF, then deposited on glass slides covered with laminin (0.25×10⁶ cellsper slide), which are then placed in Corning 12-well plates. The cellsare incubated at 37° C. in a humidified atmosphere containing 5% CO₂ and95% air. Cytosine [3-D-arabinoside (1 μM) is added 48 h after cultureset-up, to prevent the development of non-neuronal cells. The slides aretransferred to the test chambers for patch-clamp investigations after7-10 days in culture.

Electrophysiology:

The measuring chambers (volume 800 μl) containing the cellularpreparation are placed on the stage of an inverted microscope (OlympusIMT2) fitted with Hoffman optics (Modulation Contrast, New York) and areobserved at magnification of 400×. The chambers are continually perfusedby gravity (2.5 ml/min) by means of a solution distributor accepting 8inlets and whose single outlet, comprising a polyethylene tube (insidediameter 500 μm) is positioned at less than 3 mm from the cell underinvestigation. The “whole-cell” configuration of the patch-clamptechnique was used. Pipettes of borosilicate glass (resistance 5-10MOhms) are brought up to the cell by means of a piezoelectric 3Dmicromanipulator (Burleigh, PC1000). The total currents (membranepotential fixed at −60 mV) were recorded with an Axopatch 1D amplifier(Axon Instruments, Foster City, Calif.), connected to a PC controlled byPclamp8 software (Axon Instrument). The current traces are recorded onpaper and simultaneously digitized (sampling frequency 15 to 25 Hz) andsaved to the hard disk of the PC.

The application of a micromolar solution of capsaicin induces a cationicinput current on the DRG cells (voltage fixed at −70 mV). In order tominimize the desensitization of the receptors, a minimum interval of oneminute is observed between two applications of capsaicin. After acontrol period (stabilization of the capsaicin response alone), the testcompounds are applied alone at a specified concentration (concentrationof 10 nM or of 0.1 nM) for a duration of 4 to 5 minutes, during whichseveral capsaicin+compound tests are performed (for obtaining maximuminhibition). The results are expressed as percentage inhibition of thecapsaicin control response.

The percentage inhibition of the capsaicin response (1 microM) isbetween 20% and 100% for the most active compounds of the inventiontested at a concentration from 10 nM to 0.1 nM (see example in Table 5).

The compounds of the invention are therefore effective antagonists invitro of the type TRPV1 receptors.

TABLE 5 Compound No. Percentage inhibition in patch DRG 4 98% (1 nM) 671% (1 nM) 15 100% (10 nM)

Mouse Cornea Irritation Test

The irritant nature of capsaicin is easily appreciated at the level ofthe cornea since this organ is one of the most innervated with theC-fibres. In this context, according to preliminary experiments, theapplication of a very small amount of capsaicin (2 μl at a concentrationof 160 μM) to the surface of the cornea of an animal leads to a certainnumber of stereotypical behaviors associated with irritation, which areeasily listed. These include: blinking, rubbing of the instilled eye bythe ipsilateral forepaw, rubbing of the face with both forepaws,scratching of the ipsilateral face by the hindpaw. The duration of thesebehaviors does not exceed 2 minutes of observation, and the animal thenresumes its normal activity. Moreover, its appearance is also normal.The mouse does not retreat to a corner with its hair standing on end,and does not develop any observable sign of suffering. It can beconcluded that the duration of action of capsaicin at these doses isless than 2 minutes.

SUMMARY OF THE METHODOLOGY

The principle of the series of tests is to determine whether thecompounds of the invention can influence the behavioral response inducedby a specified amount of capsaicin. The capsaicin is initially dilutedto 25 mM in DMSO and diluted, for final use, in physiological serum withTween 80 at 10%. It appears, from control studies, that in theseconditions the solvent has no effect.

In practice, the test product, prepared at 25 mM in DMSO and diluted forfinal use in physiological serum with 10% of Tween 80 at the strongestconcentration of 500 μM, is administered by local application to thesurface of the cornea at a volume of 2 μl, 10 minutes before applicationof the capsaicin. The animal receives an ocular instillation of 2 μl ofa 160 μM capsaicin solution prepared as stated above. For an observationperiod of 2 minutes following instillation, the number of times theinstilled eye is rubbed by the ipsilateral forepaw is counted for eachanimal.

For a given group, the percentage protection is calculated as follows:

P=100−((average number of scratchings of the group treated with thecompound/average number of scratchings of the group treated with thesolvent)×100)

This percentage protection is averaged for each group of animals(n=number of animals tested with the compound of the invention).

The percentage protection evaluated, in this model, for the most activecompounds of the invention, used at a concentration of 500 μM, isbetween 20% and 100% (see example in Table 6):

TABLE 6 Compound No. % P 500 μM 1 51% 3 34% 6 30% 9 43% 12 83%

The results of these tests show that the most active compounds of theinvention block the effects induced by stimulation of the TRPV1receptors.

The compounds of the invention can therefore be used for the preparationof medicinal products, notably for the preparation of a medicinalproduct intended for preventing or treating pathologies involving typeTRPV1 receptors.

Thus, according to another of its aspects, the invention relates tomedicinal products that contain a compound of formula (I), or apharmaceutically acceptable salt, or a hydrate or a solvate of saidcompound.

These medicinal products find application in therapeutics, notably inthe prevention and/or treatment of pain and of inflammation, of chronicpain, neuropathic pain (traumatic, diabetic, metabolic, infectious,toxic, induced by anticancer treatment or iatrogenic), (osteo-)arthritic pain, rheumatic pain, fibromyalgia, back pain, pain associatedwith cancer, facial neuralgia, headaches, migraine, dental pain, burns,sunstroke, bites or stings, postherpetic neuralgia, muscular pain, nervecompression (central and/or peripheral), injuries of the spinal cordand/or brain, ischaemia (of the spinal cord and/or brain),neurodegeneration, hemorrhagic vascular accidents (of the spinal cordand/or brain), pain following stroke.

The compounds of the invention can be used for the preparation of amedicinal product intended for the prevention and/or treatment ofurological disorders such as overactive bladder, hyperreflexia of thebladder, bladder instability, incontinence, urinary urgency, urinaryincontinence, cystitis, nephritic colic, pelvic hypersensitivity andpelvic pain.

The compounds of the invention can be used for the preparation of amedicinal product intended for the prevention and/or treatment ofgynecological disorders such as vulvodynia, pains associated withsalpingitis, or with dysmenorrhea.

These products can also be used for the preparation of a medicinalproduct intended for the prevention and/or treatment of gastrointestinaldisorders such as gastro-oesophageal reflux disease, gastric ulcer,duodenal ulcer, functional dyspepsia, colitis, IBS, Crohn's disease,pancreatitis, oesophagitis, hepatic colic.

The compounds of the invention can also be used for the preparation of amedicinal product intended for preventing and/or treating metabolicdisorders such as diabetes.

In addition, the products of the present invention can be used in theprevention and/or treatment of respiratory disorders such as asthma,cough, COPD, bronchoconstriction and inflammatory disorders. Theseproducts can also be used for preventing and/or treating psoriasis,pruritus, irritation of the skin, eyes or mucosa, herpes simplex, herpeszoster.

The compounds of the invention can also be used for the preparation of amedicinal product intended for the treatment of depression.

According to another of its aspects, the present invention relates topharmaceutical compositions comprising, as active principle, a compoundaccording to the invention.

Said pharmaceutical compositions contain an effective dose of at leastone compound according to the invention, or a pharmaceuticallyacceptable salt, a hydrate or solvate of said compound, as well as atleast one pharmaceutically acceptable excipient. Said excipients areselected according to the pharmaceutical form and the desired method ofadministration, from the usual excipients that are known by a personskilled in the art.

In the pharmaceutical compositions of the present invention for oral,sublingual, subcutaneous, intramuscular, intravenous, topical, local,endotracheal, intranasal, transdermal or rectal administration, theactive principle of formula (I) above, or its salt, solvate or hydrateif necessary, can be administered as a unit dosage form, mixed withconventional pharmaceutical excipients, to animals and to humans for theprophylaxis or the treatment of the disorders or diseases mentionedabove.

The appropriate unit dosage forms include the forms by the oral routesuch as tablets, soft or hard capsules, powders, granules and oralsolutions or suspensions, sublingual, buccal, endotracheal, intraocular,intranasal dosage forms, by inhalation, topical, transdermal,subcutaneous, intramuscular or intravenous dosage forms, rectal dosageforms and implants. For topical application, the compounds according tothe invention can be used in creams, gels, ointments or lotions.

As an example, a unit dosage form of a compound according to theinvention in tablet form can comprise the following constituents:

Compound according to the invention 50.0 mg Mannitol 223.75 mgCroscarmellose sodium 6.0 mg Maize starch 15.0 mg Hydroxypropylmethylcellulose 2.25 mg Magnesium stearate 3.0 mg

Said unit forms are dosed to permit a daily administration of 0.001 to30 mg of active principle per kg of body weight, depending on thegalenical form.

There may be special cases when higher or lower dosages are appropriate;said dosages are still within the scope of the invention. According tothe usual practice, the dosage appropriate to each patient is determinedby the doctor according to the method of administration, and saidpatient's weight and response.

The present invention, according to another of its aspects, also relatesto a method of treatment of the aforementioned pathologies thatcomprises the administration, to a patient, of an effective dose of acompound according to the invention, or one of its pharmaceuticallyacceptable salts or hydrates or solvates.

1. A compound of the formula (I):

wherein: the pyrrolopyridine nucleus is a pyrrolo[2,3-c]pyridine group;and wherein the pyrrolopyridine nucleus being optionally substituted atcarbon positions 4, 5 or 7 with one or more substituents X, which may beidentical to or different from one another, selected from hydrogen,halogen, C₁-C₆-alkyl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkylene,C₁-C₆-fluoroalkyl, C₁-C₆-alkoxyl, C₃-C₇-cycloalkoxyl,C₃-C₇-cycloalkyl-C₁-C₆-alkylene-O—, C₁-C₆-fluoroalkoxyl, cyano,C₁-C₆-thioalkyl, —S(O)—C₁-C₆-alkyl, —S(O)₂—C₁-C₆-alkyl, SF₅, C(O)NR₁R₂,SO₂NR₁R₂, nitro, NR₁R₂, OCONR₁R₂, NR₃COR₄, NR₃CONR₁R₂, NR₃SO₂R₅,NR₃SO₂NR₁R₂, aryl-C₁-C₆-alkylene, heteroaryl-C₁-C₆-alkylene, aryl andheteroaryl; wherein the aryl and the heteroaryl being optionallysubstituted with one or more substituents selected from halogen,C₁-C₆-alkyl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkylene,C₁-C₆-fluoroalkyl, C₁-C₆-alkoxyl, C₁-C₆-fluoroalkoxyl, nitro and cyano;n is equal to 0, 1, 2 or 3; Y represents aryl or heteroaryl; the aryl orthe heteroaryl being optionally substituted with one or more groupsselected from a halogen atom or a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₆-alkylene, C₁-C₆-fluoroalkyl, hydroxyl,C₁-C₆-alkoxyl, C₃-C₇-cycloalkoxyl, C₃-C₇-cycloalkyl-C₁-C₆-alkylene-O—,C₁-C₆-fluoroalkoxyl, cyano, C₁-C₆-thioalkyl, thiol, —S(O)—C₁-C₆-alkyl,—S(O)₂—C₁-C₆-alkyl, C(O)NR₁R₂, SO₂NR₁R₂, SF₅, nitro, OCONR₁R₂, NR₃COR₄,NR₃CONR₁R₂, NR₁R₂, NR₃SO₂NR₁R₂, NR₃COR₄, NR₃SO₂R₅, aryl-C₁-C₆-alkyleneand aryl; wherein the aryl and the aryl-C₁-C₆-alkylene being optionallysubstituted with one or more substituents selected from halogen,C₁-C₆-alkyl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkylene,C₁-C₆-fluoroalkyl, C₁-C₆-alkoxyl, C₁-C₆-fluoroalkoxyl, nitro and cyano;Z₁, Z₂, Z₃, Z₄ represent, independently of one another, nitrogen orC(R₆), wherein at least one corresponding to nitrogen and at least onecorresponding to C(R₆); and wherein one of the nitrogen atoms present inthe ring, defined as position-1 nitrogen, being optionally substitutedwith R₇ when the carbon atom in position 2 or 4 relative to thisreference nitrogen is substituted with an oxo or thio group; Zrepresents either a cyclic amine attached by the nitrogen atom, offormula:

in which A represents a C₁-C₇-alkylene group optionally substituted withone or two groups R₈, B represents a C₁-C₇-alkylene group optionallysubstituted with one or two groups R₉, L represents a bond, sulfur,oxygen or nitrogen atom; the nitrogen atom being optionally substitutedwith a group R₁₀ or R₁₁; the carbon atoms of the cyclic amine Z beingoptionally substituted with one or more groups R₁₂ which may beidentical to or different from one another; or an acyl amine, attachedby the nitrogen atom, of formula NRaRb in which Ra and Rb represent,independently of one another, hydrogen, C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₆-alkylene, C₁-C₆-fluoroalkyl, hydroxyl,C₁-C₆-alkoxyl, C₃-C₇-cycloalkyl-C₁-C₆-alkylene-O—, C₁-C₆-fluoroalkoxyl,C₁-C₆-alkyl-C(O)—, HO—C(O)—C₁-C₆-alkylene,C₁-C₆-alkyl-O—C(O)—C₁-C₆-alkylene, aryl or heteroaryl group, and Ra andRb can optionally be substituted with one or more groups Rc which may beidentical to or different from one another; Rc represents a halogenatom, a C₁-C₆-alkyl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkylene,C₁-C₆-fluoroalkyl, C₁-C₆-alkoxyl, C₃-C₇-cycloalkyl-C₁-C₆-alkylene-O—,C₁-C₆-fluoroalkoxyl, C₁-C₆-thioalkyl, —S(O)—C₁-C₆-alkyl,—S(O)₂—C₁-C₆-alkyl, cyano, C(O)NR₁R₂, NR₁R₂, SO₂NR₁, R₂, NR₃COR₄,NR₃SO₂R₅, OC(O)NR₁R₂, NR₃COOR₅, NR₃CONR₁R₂, NR₃SO₂NR₁R₂, hydroxyl,thiol, oxo, thio, aryl-C₁-C₆-alkylene, aryl or heteroaryl group, thearyl and the heteroaryl being optionally substituted with one or moresubstituents selected from a halogen, a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₆-alkylene, C₁-C₆-fluoroalkyl, C₁-C₆-alkoxyl,C₁-C₆-fluoroalkoxyl, nitro or cyano group; R₁ and R₂ represent,independently of one another, hydrogen, C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₆-alkylene, aryl-C₁-C₆-alkylene, aryl or heteroarylgroup, the aryl and the heteroaryl being optionally substituted with oneor more substituents selected from a halogen, a C₁-C₆-alkyl,C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkylene, C₁-C₆-fluoroalkyl,C₁-C₆-alkoxyl, C₁-C₆-fluoroalkoxyl, nitro or cyano group; or R₁ and R₂taken together with the nitrogen atom to which they are attached form acyclic ring selected from the group consisting of azetidinyl,pyrrolidinyl, piperidinyl, azepinyl, morpholinyl, thiomorpholinyl,piperazinyl and homopiperazinyl; said ring being optionally substitutedwith a C₁-C₆-alkyl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkylene,aryl-C₁-C₆-alkylene, aryl or heteroaryl group, the aryl and theheteroaryl being optionally substituted with one or more substituentsselected from a halogen, a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₆-alkylene, C₁-C₆-fluoroalkyl, C₁-C₆-alkoxyl,C₁-C₆-fluoroalkoxyl, nitro or cyano group; R₃ and R₄ represent,independently of one another, hydrogen, C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₆-alkylene, aryl-C₁-C₆-alkylene, aryl or heteroarylgroup, the aryl and the heteroaryl being optionally substituted with oneor more substituents selected from a halogen, a C₁-C₆-alkyl,C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkylene, C₁-C₆-fluoroalkyl,C₁-C₆-alkoxyl, C₁-C₆-fluoroalkoxyl, nitro or cyano group; or R₃ and R₄together form a (C₂-C₅)alkylene group; or R₁ and R₃ together form a(C₂-C₅)alkylene group; R₅ represents a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₆-alkylene, aryl-C₁-C₆-alkylene, aryl or heteroarylgroup, the aryl and the heteroaryl being optionally substituted with oneor more substituents selected from a halogen, a C₁-C₆-alkyl,C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkylene, C₁-C₆-fluoroalkyl,C₁-C₆-alkoxyl, C₁-C₆-fluoroalkoxyl, nitro or cyano group; or R₃ and R₅together form a (C₂-C₅)alkylene group; R₆ represents a hydrogen orhalogen atom or a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₆-alkylene, C₁-C₆-fluoroalkyl, C₁-C₆-alkoxyl,C₃-C₇-cycloalkoxyl, C₃-C₇-cycloalkyl-C₁-C₆-alkylene-O—,C₁-C₆-fluoroalkoxyl, C₁-C₆-thioalkyl, —S(O)—C₁-C₆-alkyl,—S(O)₂—C₁-C₆-alkyl, hydroxyl, thiol, oxo, thio, aryl,aryl-C₁-C₆-alkylene, heteroaryl group, the aryl and the heteroaryl beingoptionally substituted with one or more substituents selected from ahalogen, a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₆-alkylene, C₁-C₆-fluoroalkyl, C₁-C₆-alkoxyl,C₁-C₆-fluoroalkoxyl, nitro or cyano group; R₇ represents a hydrogenatom, a C₁-C₆-alkyl, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkylene,C₁-C₆-fluoroalkyl, C₁-C₆-alkoxyl, C₃-C₇-cycloalkoxyl,C₃-C₇-cycloalkyl-C₁-C₆-alkylene-O—, C₁-C₆-fluoroalkoxyl, aryl,aryl-C₁-C₆-alkylene or heteroaryl group, the aryl and the heteroarylbeing optionally substituted with one or more substituents selected froma halogen, a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₆-alkylene, C₁-C₆-fluoroalkyl, C₁-C₆-alkoxyl,C₁-C₆-fluoroalkoxyl, nitro or cyano group; R₈, R₉ and R₁₀ are definedsuch that: two groups R₈ can together form a linkage or a C₁-C₆-alkylenegroup; two groups R₉ can together form a linkage or a C₁-C₆-alkylenegroup; R₈ and R₉ can together form a linkage or a C₁-C₆-alkylene group;R₈ and R₁₀ can together form a linkage or a C₁-C₆-alkylene group; R₉ andR₁₀ can together form a linkage or a C₁-C₆-alkylene group; R₁₁represents a hydrogen atom, a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₆-alkylene, C₁-C₆-fluoroalkyl, C₁-C₆-alkoxyl,C₃-C₇-cycloalkoxyl, C₃-C₇-cycloalkyl-C₁-C₆-alkylene-O—,C₁-C₆-fluoroalkoxyl, hydroxyl, C₁-C₆-alkyl-CO—, COOR₅, C(O)NR₁R₂,aryl-C₁-C₆-alkylene, aryl or heteroaryl group, the aryl and theheteroaryl being optionally substituted with one or more substituentsselected from a halogen, a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₆-alkylene, C₁-C₆-fluoroalkyl, C₁-C₆-alkoxyl,C₃-C₇-cycloalkoxyl, C₁-C₆-fluoroalkoxyl, nitro or cyano group; R₁₂represents a fluorine atom, a C₁-C₆-alkyl group optionally substitutedwith an R₁₃, C₃-C₇-cycloalkyl, C₃-C₇-cycloalkyl-C₁-C₆-alkylene,C₁-C₆-fluoroalkyl, C₁-C₆-cycloalk-1,1-diyl,C₃-C₇-heterocycloalk-1,1-diyl group optionally substituted on a nitrogenatom with an R₁₁, C₁-C₆-alkoxyl, C₃-C₇-cycloalkoxyl,C₃-C₇-cycloalkyl-C₁-C₆-alkylene-O—, C₁-C₆-fluoroalkoxyl, CO₂H,C(O)O—C₁-C₆-alkyl, C(O)NR₁R₂, NR₁R₂, NR₃COR₄, OC(O)NR₁R₂, NR₃COOR₅,NR₃CONR₁R₂, hydroxyl, thiol, oxo, thio, aryl-C₁-C₆-alkylene, aryl group,the aryl being optionally substituted with one or more substituentsselected from a halogen, a C₁-C₆-alkyl, C₃-C₇-cycloalkyl,C₃-C₇-cycloalkyl-C₁-C₆-alkylene, C₁-C₆-fluoroalkyl, C₁-C₆-alkoxyl,C₃-C₇-cycloalkoxyl, C₁-C₆-fluoroalkoxyl, nitro or cyano group; and R₁₃represents a C₁-C₆-alkoxy, C₃-C₇-cycloalkoxyl,C₃-C₇-cycloalkyl-C₁-C₆-alkylene-O—, C(O)NR₁R₂, NR₁R₂, NR₃COR₄,OC(O)NR₁R₂, NR₃COOR₅, hydroxyl group; or an N-oxide thereof or a saltthereof.
 2. The compound of formula (I) according to claim 1, whereinthe substituent or substituents X, which may be identical to ordifferent from one another, are selected from hydrogen, halogen orC₁-C₆-fluoroalkyl.
 3. The compound of formula (I) according to claim 1,wherein n is equal to
 1. 4. The compound of formula (I) according toclaim 1, wherein Y represents an aryl or a heteroaryl, the aryl or theheteroaryl being optionally substituted with one or more groups selectedfrom halogen, C₁-C₆-alkyl, C₁-C₆-fluoroalkyl, C₁-C₆-alkoxyl orC₁-C₆-fluoroalkoxyl.
 5. The compound of formula (I) according to claim1, wherein: Z₁, Z₂, Z₃, Z₄ represent, independently of one another,nitrogen or C(R₆), at least one corresponding to nitrogen and at leastone corresponding to C(R₆); R₆ represents hydrogen, halogen,C₁-C₆-alkyl, C₁-C₆-fluoroalkyl or C₁-C₆-alkoxyl.
 6. The compound offormula (I) according to claim 1, wherein: Z represents either a cyclicamine attached by the nitrogen atom, of formula:

in which A represents a C₁-C₇-alkylene group optionally substituted withone or two groups R₈; B represents a C₁-C₇-alkylene group optionallysubstituted with one or two groups R₉; L represents a linkage; thecarbon atoms of the cyclic amine Z being optionally substituted with oneor more groups R₁₂ which may be identical to or different from oneanother; R₁₂ represents a fluorine atom, a C₁-C₆-alkyl, C₁-C₆-alkoxyl,C₃-C₇-cycloalkyl-C₁-C₆-alkylene-O—, CO₂H, C(O)O—C₁-C₆-alkyl or hydroxylgroup; R₈ and R₉ are defined such that: two groups R₈ can together forma linkage or a C₁-C₆-alkylene group; two groups R₉ can together form alinkage or a C₁-C₆-alkylene group; R₈ and R₉ can together form a linkageor a C₁-C₆-alkylene group; or an acyl amine, attached by the nitrogenatom, of formula NRaRb in which Ra and Rb represent, independently ofone another, a hydrogen atom or a C₁-C₆-alkyl, C₁-C₆-alkyl-C(O)—,HO—C(O)—C₁-C₆-alkylene or C₁-C₆-alkyl-O—C(O)—C₁-C₆-alkylene, and Ra andRb can optionally be substituted with a group Rc where Rc represents ahydroxyl.
 7. The compound of formula (I) according to claim 6, wherein:Z represents either a cyclic amine attached by the nitrogen atom, offormula:

in which A represents a C₁-C₇-alkylene group optionally substituted witha group R₈; B represents a C₁-C₇-alkylene group optionally substitutedwith a group R₉; L represents a linkage; the carbon atoms of the cyclicamine Z being optionally substituted with one or more groups R₁₂ whichmay be identical to or different from one another; R₁₂ represents afluorine atom, a C₁-C₆-alkyl, C₁-C₆-alkoxyl,C₃-C₇-cycloalkyl-C₁-C₆-alkylene-O—, CO₂H, C(O)O—C₁-C₆-alkyl or hydroxylgroup; R₈ and R₉ are defined such that: R₈ and R₉ can together form alinkage; or an acyl amine, attached by the nitrogen atom, of formulaNRaRb in which Ra and Rb represent, independently of one another, ahydrogen atom or a C₁-C₆-alkyl, C₁-C₆-alkyl-C(O)—,HO—C(O)—C₁-C₆-alkylene or C₁-C₆-alkyl-O—C(O)—C₁-C₆-alkylene group, andRa and Rb can optionally be substituted with a group Rc where Rcrepresents a hydroxyl.
 8. The compound of formula (I) according to claim7, wherein: Z represents either a cyclic amine attached by the nitrogenatom and selected from the pyrrolidinyl, azetidinyl,azabicyclo[3.2.0]heptyl or azabicyclo[3.1.0]hexyl groups, the carbonatoms of the cyclic amine being optionally substituted with one or moregroups R₁₂ which may be identical to or different from one another; R₁₂represents a fluorine atom, a C₁-C₆-alkyl, C₁-C₆-alkoxyl,C₃-C₇-cycloalkyl-C₁-C₆-alkylene-O—, CO₂H, C(O)O—C₁-C₆-alkyl or hydroxylgroup; or an acyl amine, attached by the nitrogen atom, of formula NRaRbin which Ra and Rb represent, independently of one another, a hydrogenatom or a C₁-C₆-alkyl, C₁-C₆-alkyl-C(O)—, HO—C(O)—C₁-C₆-alkylene orC₁-C₆-alkyl-O—C(O)—C₁-C₆-alkylene group, and Ra and Rb can optionally besubstituted with a group Rc where Rc represents a hydroxyl.
 9. Thecompound of formula (I) according to claim 1, wherein: thepyrrolopyridine nucleus is a pyrrolo[2,3-c]pyridine group; thesubstituent or substituents X, which may be identical to or differentfrom one another, are selected from a hydrogen or halogen atom or aC₁-C₆-fluoroalkyl group; n is equal to 1; Y represents an aryl or aheteroaryl, the aryl or the heteroaryl being optionally substituted withone or more groups selected from a halogen atom or a C₁-C₆-alkyl,C₁-C₆-fluoroalkyl, C₁-C₆-alkoxyl or C₁-C₆-fluoroalkoxyl group; Z₁, Z₂,Z₃, Z₄ represent, independently of one another, a nitrogen atom or agroup C(R₆), at least one corresponding to a nitrogen atom and at leastone corresponding to a group C(R₆); R₆ represents a hydrogen or halogenatom or a C₁-C₆-alkyl, C₁-C₆-fluoroalkyl or C₁-C₆-alkoxyl group; Zrepresents either a cyclic amine attached by the nitrogen atom andselected from the pyrrolidinyl, azetidinyl, azabicyclo[3.2.0]heptyl orazabicyclo[3.1.0]hexyl groups, the carbon atoms of the cyclic aminebeing optionally substituted with one or more groups R₁₂ which may beidentical to or different from one another; R₁₂ represents a fluorineatom, a C₁-C₆-alkyl, C₁-C₆-alkoxyl, C₃-C₇-cycloalkyl-C₁-C₆-alkylene-O—,CO₂H, C(O)O—C₁-C₆-alkyl or hydroxyl group; or an acyl amine, attached bythe nitrogen atom, of formula NRaRb in which Ra and Rb represent,independently of one another, a hydrogen atom or a C₁-C₆-alkyl,C₁-C₆-alkyl-C(O)—, HO—C(O)—C₁-C₆-alkylene orC₁-C₆-alkyl-O—C(O)—C₁-C₆-alkylene group, and Ra and Rb can optionally besubstituted with a group Rc where Rc represents a hydroxyl.
 10. A methodof preparation of a compound of formula (I) according to claim 1comprising: reacting a compound of formula (IV) in a solvent:

in which the pyrrolopyridine nucleus is a pyrrolo[2,3-c]pyridine group;X, Y and n are as defined in claim 1 and B represents a chlorine atom,with an amine of general formula (V):

in which W═Z and Z, Z₁, Z₂, Z₃ and Z₄ are as defined in claim
 1. 11. Amethod of preparation of a compound of formula (I) according to claim 1comprising: reacting a compound of general formula (IV):

the pyrrolopyridine nucleus is a pyrrolo[2,3-c]pyridine group; X, Y andn are as defined in claim 1 and B represents a hydroxyl group, with anamine of general formula (V):

in which W═Z and Z, Z₁, Z₂, Z₃ and Z₄ are as defined in claim 1, in thepresence of a coupling agent, and optionally a base, in a solvent.
 12. Amethod of preparation of a compound of formula (I) according to claim 1comprising: reacting a compound of general formula (VI):

in which the pyrrolopyridine nucleus is a pyrrolo[2,3-c]pyridine group;X, Y, n, Z₁, Z₂, Z₃ and Z₄ are as defined in claim 1 and W represents ahalogen atom, with an amine of formula Z—H, in which Z is as defined inclaim
 1. 13. A pharmaceutical composition comprising a compound offormula (I) according to claim 1 or a pharmaceutically acceptable saltthereof in combination with at least one pharmaceutically acceptableexcipient.
 14. A pharmaceutical composition comprising a compound offormula (I) according to claim 2 or a pharmaceutically acceptable saltthereof in combination with at least one pharmaceutically acceptableexcipient.
 15. A pharmaceutical composition comprising a compound offormula (I) according to claim 3 or a pharmaceutically acceptable saltthereof in combination with at least one pharmaceutically acceptableexcipient.
 16. A pharmaceutical composition comprising a compound offormula (I) according to claim 4 or a pharmaceutically acceptable saltthereof in combination with at least one pharmaceutically acceptableexcipient.
 17. A pharmaceutical composition comprising a compound offormula (I) according to claim 5 or a pharmaceutically acceptable saltthereof in combination with at least one pharmaceutically acceptableexcipient.
 18. A pharmaceutical composition comprising a compound offormula (I) according to claim 6 or a pharmaceutically acceptable saltthereof in combination with at least one pharmaceutically acceptableexcipient.
 19. A pharmaceutical composition comprising a compound offormula (I) according to claim 7 or a pharmaceutically acceptable saltthereof in combination with at least one pharmaceutically acceptableexcipient.
 20. A pharmaceutical composition comprising a compound offormula (I) according to claim 8 or a pharmaceutically acceptable saltthereof in combination with at least one pharmaceutically acceptableexcipient.
 21. A pharmaceutical composition comprising a compound offormula (I) according to claim 9 or a pharmaceutically acceptable saltthereof in combination with at least one pharmaceutically acceptableexcipient.
 22. A method of treating a disease selected from the groupconsisting of pain and irritation of the skin, eyes and mucous membrane,comprising administering to a patient in need of said treatment atherapeutically effective amount of a compound of formula (I) accordingto claim
 1. 23. A method of treating a disease selected from the groupconsisting of pain and irritation of the skin, eyes and mucous membrane,comprising administering to a patient in need of said treatment atherapeutically effective amount of a compound of formula (I) accordingto claim
 2. 24. A method of treating a disease selected from the groupconsisting of pain and irritation of the skin, eyes and mucous membrane,comprising administering to a patient in need of said treatment atherapeutically effective amount of a compound of formula (I) accordingto claim
 3. 25. A method of treating a disease selected from the groupconsisting of pain and irritation of the skin, eyes and mucous membrane,comprising administering to a patient in need of said treatment atherapeutically effective amount of a compound of formula (I) accordingto claim
 4. 26. A method of treating a disease selected from the groupconsisting of pain and irritation of the skin, eyes and mucous membrane,comprising administering to a patient in need of said treatment atherapeutically effective amount of a compound of formula (I) accordingto claim
 5. 27. A method of treating a disease selected from the groupconsisting of pain and irritation of the skin, eyes and mucous membrane,comprising administering to a patient in need of said treatment atherapeutically effective amount of a compound of formula (I) accordingto claim
 6. 28. A method of treating a disease selected from the groupconsisting of pain and irritation of the skin, eyes and mucous membrane,comprising administering to a patient in need of said treatment atherapeutically effective amount of a compound of formula (I) accordingto claim
 7. 29. A method of treating a disease selected from the groupconsisting of pain and irritation of the skin, eyes and mucous membrane,comprising administering to a patient in need of said treatment atherapeutically effective amount of a compound of formula (I) accordingto claim
 8. 30. A method of treating a disease selected from the groupconsisting of pain and irritation of the skin, eyes and mucous membrane,comprising administering to a patient in need of said treatment atherapeutically effective amount of a compound of formula (I) accordingto claim 9.